Vasculature and lymphatic system imaging and ablation

ABSTRACT

In an embodiment, an untethered device includes one or more first energy sources configured to provide energy to elicit one or more image responses associated with one or more blood vessels or lymph vessels. The device includes one or more sensors configured to capture the one or more image responses. Control circuitry is provided and coupled to the sensors for at least partially identifying one or more targets at least partially based on the captured one or more image responses. One or more inserts are provided, which are configured to be disposed in the one or more blood vessels or lymph vessels, and slow or trap the blood vessels or lymph vessels therein. One or more second energy sources are provided for ablating the one or more targets when they are slowed or trapped by the one or more inserts.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is related to U.S. patent application Ser. No.11/973,357, entitled VASCULATURE AND LYMPHATIC SYSTEM IMAGING ANDABLATION ASSOCIATED WITH A LOCAL BYPASS, naming Roderick A. Hyde, EdwardK. Y. Jung, Nathan P. Myhrvold, Clarence T. Tegreene, Willard H.Wattenburg, Lowell L. Wood, Jr. and Richard N. Zare as inventors, filed4 Oct. 2007.

The present application is related to U.S. patent application Ser. No.11/973,367, entitled VASCULATURE AND LYMPHATIC SYSTEM IMAGING ANDABLATION ASSOCIATED WITH A RESERVOIR, naming Roderick A. Hyde, Edward K.Y. Jung, Nathan P. Myhrvold, Clarence T. Tegreene, Willard H.Wattenburg, Lowell L. Wood, Jr. and Richard N. Zare as inventors, filed5 Oct. 2007.

All subject matter of the Related Applications and of any and allparent, grandparent, great-grandparent, etc. applications of the RelatedApplications is incorporated herein by reference to the extent suchsubject matter is not inconsistent herewith.

SUMMARY

The present application relates, in general, to devices and methods forimaging and ablation of medical targets. Such devices and methods areuseful for ablating target cells and/or tissues as well as treatment,prevention, and/or diagnosis of a variety of diseases and disorders.Devices are configured to be used internally and untethered. Variousmethods include using one or more of the devices for ablating targetcells within the vascular or lymphatic systems. Illustrative examplesinclude using one or more of the devices or methods to treat and/orablate blood-borne pathogens and/or neoplasms.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, further aspects, embodiments, and featureswill become apparent by reference to the drawings and the followingdetailed description.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a schematic of an illustrative device in which embodimentsmay be implemented.

FIG. 2 shows a schematic of illustrative embodiments of the device ofFIG. 1, with illustrative examples of an energy source.

FIG. 3 shows a schematic of illustrative embodiments of the device ofFIG. 1, with illustrative examples of an optical energy source.

FIG. 4 shows a schematic of illustrative embodiments of the device ofFIG. 1, with illustrative examples of a sensor.

FIG. 5 shows a schematic of illustrative embodiments of the device ofFIG. 1, with illustrative examples of an electromagnetic energy sensor.

FIG. 6 shows a schematic of illustrative embodiments of the device ofFIG. 1, with illustrative examples of a power source.

FIG. 7 and FIG. 8 show schematics of an illustrative device including alocal bypass in which embodiments may be implemented.

FIG. 9 and FIG. 10 show schematics of an illustrative device including areservoir in which embodiments may be implemented.

FIG. 11 shows a schematic of an illustrative embodiment of a systemincluding a device in use on a subject.

FIG. 12, FIG. 13, FIG. 14, FIG. 15, FIG. 16 and FIG. 17 show schematicsof illustrative embodiments of systems including devices configured tofunction in a vessel lumen.

FIG. 18, FIG. 19, and FIG. 20 show schematics of illustrativeembodiments of systems including devices configured to function proximalto a vessel lumen optionally including a reservoir.

FIG. 21, FIG. 22, FIG. 23, and FIG. 24 show schematics of illustrativeembodiments of systems including devices including a local bypass andoptionally including a reservoir.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here.

The present application relates, in general, to systems, devices, andmethods for imaging and optionally ablating medical targets in thevasculature and lymphatic systems for treatment, prevention and/ordiagnosis. Those having skill in the art will appreciate that thespecific devices and methods described herein are intended as merelyillustrative of their more general counterparts.

In one aspect, FIG. 1 through FIG. 10 depict one or more embodiments ofone or more device 100, 200, and/or 300, configured to image andoptionally to ablate one or more targets or target areas. Although oneor more embodiments of one or more devices may be presented separatelyherein, it is intended and envisioned that one or more devices and/orembodiments of one or more devices, in whole or in part, may be combinedand/or substituted among the devices to encompass a full disclosure ofthe one or more devices. As disclosed below, one or more devices may beused in one or more methods of treatment, prevention, and/or diagnosisas well as methods for imaging and/or impairing targets as describedherein.

FIG. 1, FIG. 2, FIG. 3, FIG. 4, FIG. 5, and FIG. 6 depict illustrativeembodiments of one or more device 100 having one or more sensors 130configured to function in, or proximal to, one or more blood vessel orlymph vessel and to capture one or more image responses; and controlcircuitry 150 coupled to the one or more sensors 130 and responsive toat least partially identify one or more targets in real time at leastpartially based on the one or more captured image responses. The one ormore device 100 optionally includes one or more of one or more energysource 110, one or more power source 160, one or more insert 170, one ormore vessel attachment units 180, and/or one or more vessel lumenanchors 190.

FIG. 7 and FIG. 8 depict illustrative embodiments of one or more device200 having a local bypass 210 configured to function in, or proximal to,one or more blood vessel or lymph vessel; one or more sensors 130configured to function in, or proximal to, the local bypass and tocapture one or more image responses; and control circuitry 150 coupledto the one or more sensors 130 and responsive to at least partiallyidentify one or more targets in real time at least partially based onthe one or more captured image responses. The one or more device 200optionally includes one or more of one or more energy source 110, one ormore power source 160, one or more insert 170, one or more vesselattachment units 180, and/or one or more vessel lumen anchors 190.

FIG. 9 and FIG. 10 depict illustrative embodiments of one or more device300 having one or more reservoirs 310 responsive to control circuitry150, and configured to receive one or more targets and to function in,or proximal to, one or more blood vessel or lymph vessel; one or moresensors 130 configured to function in, or proximal to, the one or morereservoirs and to capture one or more image responses; and controlcircuitry 150 coupled to the one or more sensors 130 and responsive toat least partially identify one or more targets in real time at leastpartially based on the one or more captured image responses. The one ormore device 300 optionally includes one or more of one or more energysource 110, one or more power source 160, one or more insert 170, one ormore vessel attachment units 180, and/or one or more vessel lumenanchors 190.

The one or more devices 100, 200, and/or 300 in whole, or in part, areconfigured for use in, or proximal to, one or more blood vessels and/orlymph vessels of an organism. In illustrative embodiments, the one ormore device 100, 200, and/or 300, in part or in whole, is anintra-lumenally sized device (e.g. small enough to be placed in a bloodvessel and/or lymph vessel while not necessarily obstructing the flow).In illustrative embodiments, the one or more device 100, 200, and/or300, in part or in whole, is configured for use proximal to a bloodvessel or lymph vessel.

As used herein, the term “lumen” may include, but is not limited to,part or all of the open interior of a blood vessel (including e.g.,arteries, veins, and capillaries), or of a lymph vessel. As used herein,the term “proximal to” may include, but is not limited to, a spaceand/or area near to a blood or lymph vessel and/or vessel lumen.Locations that are proximal to a vessel may include, for example,locations external to the vessel wall optionally where there is spacefor implanting one or more devices in whole or in part, and optionallyto facilitate external access to the devices in whole or in part. Insome embodiments, “proximal to” may include distances such as, but notlimited to, approximately 0.1, 1.0, 10, and/or 100 μms and/or 0.1, 1.0,10, and/or 100 mms, and may optionally include larger and/or smallerdistances depending on, for example, the availability of space, the sizeof the device and/or the vessel, and the characteristics of the energy(e.g. electromagnetic energy, particle beam, two-photon, pulsed, etc.)and/or the sensors (e.g. sensitivity of detection). Those of skill inthe art would know (and/or are able to calculate) the applicabledistance for each form of energy.

The one or more devices 100, 200, and/or 300 are, in whole or in part,untethered. As used herein, the term “untethered” includes not requiredto be physically linked to one or more external components and/or notphysically linked to one or more external components. In someembodiments, untethered may include autonomous functioning, such thatthere is, for example, no required external control circuitry link aswell.

Embodiments of one or more device 100, 200, and/or 300 may be configuredas a self-contained unit that includes all functionalities necessary foroperation of the device, or configured as one or more subparts in one ormore locations separate from one another (and optionally external to thesubject), wherein one or more of the subparts includes one or moreessential and/or non-essential functionalities. In illustrativeexamples, one subpart may be placed within a lumen of, for example, ablood vessel, and another subpart placed, for example, proximal to theblood vessel optionally in a location more accessible from the exteriorof the subject, or where there is additional space. In illustrativeembodiments, a remote portion may provide for monitoring of thelumen-based device, data collection, or data analysis, and/orremote-control of one or more other functions such as image capture, andenergy use. The remote portion may be at a separate location within thebody of the subject, or outside the body of the subject. Data and/orpower signals may be transmitted between the one or more subparts usingelectromagnetic signals, for example, or electrical or optical links.Methods of distributing functionalities of a system between hardware,firmware, and software at located at two or more sites are well known tothose of skill in the art.

Embodiments of one or more device 100, 200, and/or 300 may be describedas having one or more subparts including, but not limited to, one ormore energy sources 110, one or more sensors 130, one or more controlcircuitry 150, one or more power sources 160, one or more insert 170,one or more vessel attachment units 180, and/or one or more vessel lumenanchors 190. In some embodiments, one or more subpart may be aphysically distinct unit. In some embodiments, one or more subpart iscombined with one or more other subpart to form a single unit optionallywith no physically discernible separation. Some embodiments include afirst, second, third, fourth, fifth, etc. energy source 110, sensor 130,control circuitry 150, power sources 160, insert 170, vessel attachmentunits 180, and/or vessel lumen anchors 190, for example. One or more ofthe one, two three, four, five, etc. components may be part of the samecomponent and/or physical entity, or one or more components may be aseparate physical entity. For example, there may be two lasers in adevice, or there may be one laser able to provide both excitation andablation energy. For example, there may be two sensors in a device, orthere may be one sensor able to detect a variety of energy wavelengths.

As used herein, the term “internal location” may include locationswithin the body of a subject appropriate for the placement of one ormore device and/or part of one or more device. In illustrativeembodiments, one or more internal locations may be proximal to one ormore blood vessel and/or lymph vessel. Such internal locations are knownto those with skill in the art and/or described herein. Methods forplacing one or more devices in internal locations are known to those inthe medical profession, for example. As used herein, the term “medicalprofessional” may include, but is not limited to, physicians, nurses,mid-wives, and/or nurse practitioners, dental professionals, such as butnot limited to, dentists, orthodontists, dental hygienists, andveterinary professionals, including but not limited to, veterinariansduring treatment optionally including surgery.

As used herein, the term “subject” may include, but is not limited to,one or more living entities including, but not limited to, animals,mammals, humans, reptiles, birds, amphibians, and/or fish. The animalsmay include, but are not limited to, domesticated, wild, research, zoo,sports, pet, primate, marine, and/or farm animals. Animals include, butare not limited to, bovine, porcine, swine, ovine, murine, canine,avian, feline, equine, and/or rodent animals. Domesticated and/or farmanimals include, but are not limited to, chickens, horses, cattle, pigs,sheep, donkeys, mules, rabbits, goats, ducks, geese, chickens, and/orturkeys. Wild animals include, but are not limited to, non-humanprimates, bear, deer, elk, raccoons, squirrels, wolves, coyotes,opossums, foxes, skunks, and/or cougars. Research animals include, butare not limited to, rats, mice, hamsters, guinea pigs, rabbits, pigs,dogs, cats and/or non-human primates. Pets include, but are not limitedto, dogs, cats, gerbils, hamsters, guinea pigs and/or rabbits. Reptilesinclude, but are not limited to, snakes, lizards, alligators,crocodiles, iguanas, and/or turtles. Avian animals include, but are notlimited to, chickens, ducks, geese, owls, sea gulls, eagles, hawks,and/or falcons. Fish include, but are not limited to, farm-raised, wild,pelagic, coastal, sport, commercial, fresh water, salt water, and/ortropical. Marine animals include, but are not limited to, whales,sharks, seals, sea lions, walruses, penguins, dolphins, and/or fish.

The dimensions and mechanical properties (e.g., rigidity) of the one ormore devices 100, 200, and/or 300, in part or in whole, and particularlyof the structural elements of the one or more device (e.g. one or moreinserts 170, one or more vessel attachment units 180, one or more vessellumen anchors 190, one or more local bypass 210, one or more closableopenings 213, one or more vessel insertion unit 214, one or more bypassinsert 216, one or more intralumenal reservoir 311, and/or one or moreself-sealing aperture 313, among others), may be selected forcompatibility with the location of use in order to provide for reliablepositioning and/or to provide for movement of the device whilepreventing damage to the vessel, the vessel lumen, and/or internallocation and its surrounding structure. In illustrative embodiments,part or all of a device is configured for use within a blood vessel orlymph vessel lumen. In illustrative embodiments, part or all of a deviceis configured for use proximal to (i.e. at least partially external to)a blood vessel or lymph vessel. In illustrative embodiments, at leastpart of an untethered device is internal to a subject. In illustrativeembodiments, part of an untethered device is external to a subject. Inillustrative embodiments, part or all of a device is immobile.

The choice of structural element size and configuration appropriate fora particular blood or lymph vessel location may be selected by a personof skill in the art, optionally a medical professional. Structuralelements may be constructed using a variety of manufacturing methods,from a variety of materials. Appropriate materials may include metals,ceramics, polymers, and composite materials having suitablebiocompatibility, sterilizability, mechanical, and physical properties,as will be known to those of skill in the art. Examples of materials andselection criteria are described, for example, in The BiomedicalEngineering Handbook (Second Edition, Volume I, J. D. Bronzino, Ed.,Copyright 2000, CRC Press LLC, pp. IV-1-43-22). Manufacturing techniquesmay include injection molding, extrusion, die-cutting,rapid-prototyping, etc., and will depend on the choice of material anddevice size and configuration. Sensing and energy-emitting portions ofthe devices as well as associated control circuitry may be fabricated onthe structural elements using various microfabrication and/or MEMStechniques (see, e.g., U.S. Patent Applications 2005/0221529,2005/0121411, 2005/0126916, and Nyitrai, et al. “Preparing Stents withMasking & Etching Technology” (2003) 26^(th) International SpringSeminar on Electronics Technology pp. 321-324, IEEE), or may beconstructed separately and subsequently assembled to the structuralelements, as one or more distinct components. See also, U.S. PatentApplications 2007/0066939 and 2007/0225633.

The choice of structural element size and configuration appropriate fora device may be selected by a person of skill in the art. Configurationsfor structural elements include, but are not limited to, a substantiallytubular structure, one or more lumens in fluid communication with thebody lumen, and/or an adjustable diameter (see, e.g., U.S. patentapplication Ser. Nos. 11/403,230 and 11/645,357). Structural elementsmay have the form, for example, of a short cylinder, an annulus, acylinder, and/or a spiral. A spiral structure is disclosed, for example,in Bezrouk et al, (“Temperature Characteristics of Nitinol SpiralStents” (2005) Scripta Medica (BRNO) 78(4):219-226.

In illustrative embodiments, one or more structural elements of one ormore devices may be substantially cylindrical, and hollow and tubular inconfiguration, with a single central opening, optionally allowing theexterior of the cylindrical structural element to contact and engage thewall of a vessel lumen, and the interior of the structural element(within the single central opening) to optionally form afluid-contacting portion of the structural element. Optionally, one ormore structural elements of one or more devices may be approximatelyhemi-spherical or hemi-elliptoid, optionally allowing a portion of itscross-section to contact and/or engage the wall of a lumen withoutsignificantly and/or substantially obstructing the movement of fluidwithin the body lumen. Optionally, one or more structural elements ofone or more devices may be pill- or capsule-shaped, and adapted to movethrough a central portion of a body lumen. Lumen wall engaging portionsmay include, but are not limited to, rotating wheels, projections (e.g.arms), springs, hooks (e.g. claws), suction cups, and/or tissueadhesives that are configured to engage wall portions and optionally toprovide mobility to one or more devices.

In additional to materials disclosed above, flexible material havingadjustable diameter, taper, and length properties may be used as part ofthe structural material. For example, some materials may change from alonger, narrower configuration, to a shorter, wider configuration, ormay taper over their length. Structural elements that may exhibit thistype of expansion/contraction property may include mesh structuresformed of various metals or plastics, and some polymeric materials, forexample (see, e.g., “Agile new plastics change shape with heat” MIT NewsOffice (Nov. 20, 2006) pp. 1-4; MIT Tech Talk (Nov. 22, 2006) p. 5;http://web.mit.edu/newsoffice/2006/triple-shape.html; and Shanpoor etal., Smart Materials and Structures (2005) 14:197-214, Institute ofPhysics Publishing).

In some embodiments, the structural element may include a self-expandingmaterial, a resilient material, or a mesh-like material. Flexibility mayalso be conferred by configuration as well as material; the structuralelement may include a slotted structure and/or mesh-like material, forexample. Structural elements may be formed from various materials,including metals, polymers, fabrics, and various composite materials,including ones of either inorganic or organic character, the latterincluding materials of both biologic and abiologic origin, selected toprovide suitable biocompatibility and mechanical properties. Thestructural element may include a biocompatible material, and may includea bioactive component (such as a drug releasing coating or bioactivematerial attached to or incorporated into the structural element).

Embodiments of one or more devices 100, 200, and/or 300 optionallyinclude one or more insert 170 responsive to control circuitry 150 andconfigured to modulate at least part of a vessel lumen, optionally atleast part of the circumference of the lumen. In some embodiments, oneor more insert 170 is configured to controllably, reversibly, and/orprogrammably modulate at least part of the circumference of the vessellumen. In illustrative embodiments, one or more insert 170 is configuredto reduce the diameter of at lest part of a vessel lumen responsive to asignal from control circuitry 150 optionally once every 24 hours, oronce a week, or once a month, or once a year, for example. Inillustrative embodiments, one or more insert 170 is configured tomodulate at least part of the diameter of a vessel lumen responsive to asignal from control circuitry 150 at a remote (e.g. external) location,optionally in response to a medical professional for screening and/ordiagnosis.

In some embodiments, one or more insert 170 is configured to modulate(optionally narrow, constrict, compress, and/or occlude, or expandand/or enlarge) at least part of the inner (e.g. interior) circumferenceof the vessel lumen. In some embodiments, one or more insert 170 isconfigured to modulate (e.g. optionally constrict and/or compress, orexpand and/or enlarge) at least part of the outer (e.g. exterior)circumference of the vessel lumen.

In some embodiments, one or more insert 170 is configured to narrow(e.g. compress and/or occlude) at least part of the lumen (e.g. theinner circumference and/or diameter) such that one or more cellstraverse the constriction in approximately single file and/or such thatone or more cells traverse a localized region. In some embodiments, oneor more insert 170 is configured to constrict (e.g. compress and/orocclude) at least part of the lumen (e.g. inner circumference and/ordiameter) such that fluid flow is modified and/or the movement of one ormore cells (e.g. one or more possible targets and/or one or moretargets) is decreased.

In illustrative embodiments, one or more insert 170 is configured tomodify a vessel lumen such that one or more cells traverse a localizedregion, such that the cells pass through an imaging system. An imagingsystem may include one or more sensors 130, one or more energy sources110 and/or control circuitry 150 optionally in association with the oneor more insert 170. In illustrative embodiments, one or more insert 170is configured to modify a vessel lumen such that one or more cellstraverse a localized region responsive to control circuitry 150,optionally responsive to analysis of one or more image responses (e.g.optionally identifying one or more possible targets and/or one or moretargets) from one or more sensors 130 upflow from the insert 170.

In some embodiments, one or more insert 170 is configured to functionproximal to the vessel lumen. In some embodiments, one or more insert170 is configured as a closable sleeve. In illustrative embodiments, oneor more insert 170 at least partial surrounds the vessel wall, andoptionally occludes fluid flow, by tightening around the vessel wall,optionally in discrete locations.

In some embodiments, one or more insert 170 is configured to functionwithin the vessel lumen. In some embodiments, one or more insert 170 isconfigured as an expandable tube. In some embodiments, one or moreinsert 170 includes a movable valve. In illustrative embodiments, one ormore insert 170 includes a valve that is open (e.g. not occluding fluidflow) until signaled by control circuitry 150 to partially or completelystop fluid flow. In illustrative embodiments, one or more insertincludes an expandable tube, that when expanded optionally enlarges theouter circumference of the vessel wall and/or expands or narrows theinner circumference of the vessel wall.

In some embodiments, one or more insert 170 is placed upflow from atleast one of the one or more sensors 130. In some embodiments, one ormore insert 170 is placed downflow from at least one of the one or moresensors 130. In some embodiments, one or more insert includes at leastone of the one or more sensors 130. In some embodiments, one or moresensors 130 are configured to capture one or more image responseswithin, downflow, and/or upflow of the insert modulated part of thevessel lumen. In illustrative embodiments, one or more insert 170 andone or more sensors 130 (and optionally one or more energy sources 110)are part of an imaging (and/or sensing) system. For example, an insert170 may have one or more sensor 130 (and/or energy source 110)associated upflow, optionally to screen for potential targets, one ormore sensor 130 (and/or energy source 110) positioned to detect imageswithin the insert 130, and/or one or more sensors (and/or energy source110) positioned to detect images downflow from the insert. The one ormore energy sources 110 are also optionally configured to provideablation energy to one or more targets.

In some embodiments, one or more insert 170 is placed upflow from atleast one of the one or more energy sources 110. In some embodiments,one or more insert 170 is placed downflow from at least one of the oneor more energy sources 110. In some embodiments, one or more insertincludes at least one of the one or more energy sources 110. In someembodiments, one or more energy sources 110 are configured to function(optionally elicit one or more image responses and/or provide ablationenergy) within, downflow, and/or upflow of the insert modulated part ofthe vessel lumen. In some embodiments, one or more energy sources 110are placed upflow and/or downflow of the one or more insert.

As used herein, the term “fluid” may refer to liquids, gases, and othercompositions, mixtures, or materials exhibiting fluid behavior. Thefluid within the body lumen may include a liquid, or a gas or gaseousmixtures. As used herein, the term fluid may encompass liquids, gases,or mixtures thereof that also include solid particles in a fluidcarrier. Liquids may include mixtures of two or more different liquids,solutions, slurries, or suspensions. As used herein, lumen-related fluidrefers to, blood and/or lymph. Liquids present within vessel lumens mayinclude synthetic or introduced liquids, such as blood substitutes, ordrug, nutrient, fluorescent marker, or buffered saline solutions. Fluidsmay include liquids containing dissolved gases or gas bubbles, or gasescontaining fine liquid droplets or solid particles.

As used herein, the term “downflow” includes relative locations that arein the expected subsequent path of the fluid flow (e.g. the directionfluid is flowing towards). As used herein, the term “upflow” includesrelative locations that are in the expected previous path of fluid flow(e.g. the direction fluid is flowing from).

Embodiments of one or more devices 100, 200, and/or 300 optionallyinclude one or more vessel attachment units 180. Embodiments of one ormore vessel attachment units 180 are discussed herein optionally inrelation to the local bypass 210 and reservoirs 310 among others. Insome embodiments, one or more vessel attachment units 180 may also beused for attaching systems and subparts of one or more devices 100, 200,and/or 300, optionally including energy sources 110, sensors 130,control circuitry 150, power sources 160, inserts 170, etc. proximal toa vessel wall. In illustrative embodiments, one or more vesselattachment unit 180 is configured to attach one or more insert 170proximal to one or more vessel wall.

In illustrative embodiments, one or more vessel attachment units 180include mechanisms configured to allow affixation to a vessel wall,either permanent or temporary. In illustrative embodiments,configurations for affixing may include, but are not limited to, one ormore anchors configured to attach at least temporarily to a vessel wall,one or more hooks and/or claws, one or more adhesive materials and/orglues, one or more contracting elements, and/or one or moresuction-generating elements. In illustrative embodiments, one or morevessel attachment units 180 include, but are not limited to, one or moreof sleeves, straps, clamps, Velcro (e.g. geckel), snaps, links, sutures,pins, staples, and other appropriate medical closure devices.

Embodiments of one or more devices 100, 200, and/or 300 optionallyinclude one or more vessel lumen anchors 190. Embodiments of one or morevessel lumen anchors 190 are discussed herein optionally in relation tothe local bypass 210 and reservoirs 310 among others. In someembodiments, one or more vessel lumen anchors 190 may also be used forattaching systems and subparts of one or more devices 100, 200, and/or300, optionally including energy sources 110, sensors 130, controlcircuitry 150, power sources 160, inserts 170, etc. within a vessellumen. In illustrative embodiments, one or more vessel lumen anchors 190are configured to attach one or more insert 170 within one or morevessel wall.

In illustrative embodiments, one or more vessel lumen anchors includemechanisms configured to allow affixation to a lumen wall, eitherpermanent or temporary. In illustrative embodiments, configurations foraffixing may include, but are not limited to, one or more anchorsconfigured to attach at least temporarily to a wall of the lumen, one ormore hooks and/or claws, one or more adhesive materials and/or glues,one or more expanding elements, and/or one or more suction-generatingelements.

In some embodiments, one or more configurations for affixing one or moredevices, in whole or in part, may be activated responsive to controlcircuitry 150. In some embodiments, one or more configurations foraffixing one or more devices may be fixed or movable. Movable structuresmay include, but are not limited to, mechanical elements and/ormaterials that change shape or rigidity in response to temperature,electric field, magnetic field, or various other control signals.Affixation may be permanent, for extended periods, and/or temporary. Asused herein, the term “extended periods” may include weeks to months toyears and subsets thereof. As used herein, the term “temporary” mayinclude seconds, to minutes, to hours, to days and subsets thereof.

Embodiments of one or more devices 200 include a local bypass 210 (see,e.g., FIG. 7 and FIG. 8) configured to function in, or proximal to, oneor more blood vessel or lymph vessel. In some embodiments, at least onelocation in the local bypass lumen has a circumference and/or diametersuch that one or more cells traverse the location in single file and/ortraverse a localized region, optionally to facilitate sensing and/orablation of one or more possible targets and/or one or more targets. Inillustrative embodiments, the constriction in the bypass lumen is suchthat cells larger than a certain size cannot pass (e.g. cells largerthan normal lymph cells and/or cells larger than normal constituents ofthe blood). In illustrative embodiments, the constriction in the bypasslumen is such that all cells can pass, but at a restricted velocitydepending on size (e.g. cell deformation is required to allow passage oflarger cells).

In illustrative embodiments, one or more local bypass 210 is configuredto receive fluid flow (and/or cellular flow) from a vessel. The localbypass 210 is optionally configured for enhanced imaging and/or sensingof one or more targets (e.g. funneling cells through cooperative imagingand analysis units, optionally sequential imaging and/or sensing units),facilitating treatment, prevention, and/or diagnosis of one or morediseases and/or disorders. The local bypass 210 is optionally configuredfor enhanced ablation abilities, for example such that ablation energyis provided within a confined area surrounded by bypass lumen wallsthrough which the energy does not penetrate (or does not penetrate tocollaterally damage the subject).

The local bypass is optionally configured as a system optionallyincluding, but not limited to, imaging and/or sensing systems (e.g. oneor more energy source 110, one or more control circuitry 150, and/or oneor more sensor 130), ablation systems (e.g. one or more energy source110, one or more control circuitry 150, and/or one or more sensor 130),and/or attachment/insertion systems (e.g. one or more inserts 170, oneor more bypass inserts 216, one or more vessel insertion units 214, oneor more vessel lumen anchors 190, one or more vessel attachment units180, etc.). In some embodiments, one or more of the systems are locatedwithin the local bypass 210. In some embodiments, one or more systemsare configured to function upflow and.or downflow of the local bypass210, optionally in a cooperative manner with one or more systems withinthe local bypass 210. In some embodiments, the local bypass 210 isconfigured to function cooperatively with one or more device 100 and/orone or more device 300, and/or parts thereof.

In some embodiments, the local bypass 210 is configured to function in avessel lumen (e.g. an intralumenal bypass 211), and is optionallyconfigured with one or more vessel lumen anchors 190, one or more bypassinserts 216, and/or one or more closable openings 213 (e.g. one or morevalves 215). In some embodiments, the local bypass 210 is configured tofunction proximal to a vessel lumen (e.g. an extralumenal bypass 212),and is optionally configured with at least one vessel attachment unit180 at each end of the local bypass, one or more bypass insert 216,and/or one or more vessel insertion unit 214 optionally including one ormore valves 215.

In some embodiments, one or more sensor 130 and/or one or more controlcircuitry 150 (and optionally components such as but not limited to oneor more energy source 110, one or more power source 160) are separatefrom or external to the local bypass. In some embodiments, one or moresensor 130 and/or one or more control circuitry 150 (and optionallycomponents such as but not limited to one or more energy source 110, oneor more power source 160) are part of or internal to the local bypass.In some embodiments, there are one or more sensor 130 and/or one or morecontrol circuitry 150 (and optionally components such as but not limitedto one or more energy source 110, one or more power source 160) externalto the local bypass as well as internal to the local bypass. Embodimentsin which one or more parts of the device 200 are not attached to thelocal bypass 210, may also include one or more one or more insert 170,and/or one or more vessel attachment units 180, and/or one or morevessel lumen anchors 190.

Embodiments of the local bypass 210 are optionally configured with oneor more bypass insert 216 responsive to control circuitry 150, andconfigured to modulate at least part of a local bypass lumen, optionallyat least part of the inner (e.g. interior) and/or outer (e.g. exterior)circumference and/or diameter of the lumen. Embodiments discussed inrelation to the insert 170 herein, are also applicable to the bypassinsert 216 unless context dictates otherwise.

In illustrative embodiments, the one or more bypass insert 216 is anintegral part of the local bypass 210, optionally an integral part ofthe intralumenal bypass 211 and/or the extralumenal bypass 212. Inillustrative embodiments, the one or more bypass insert 216 is anattachable, insertable, and/or additional part associated with the localbypass 210. In some embodiments, one or more bypass insert 216 isconfigured as part of the interior of (and/or to function within) thebypass lumen. In some embodiments, one or more bypass insert 216 isconfigured as part of the exterior of (and/or to function externally to)the bypass lumen. In illustrative embodiments, one or more bypass insertincludes a valve, optionally responsive to control circuitry.

In some embodiments, the one or more bypass insert 216 is configured tomodulate fluid and/or cellular flow, optionally such that movementand/or velocity of one or more possible targets and/or one or moretargets is decreased, and/or optionally increased. In illustrativeembodiments, one or more bypass insert 216 is configured as one or morevalves 215 within the lumen of the local bypass 210. For example, theone or more valves are configured to open to allow the influx of one ormore possible targets and/or one or more targets, and then to closetrapping the one or more possible targets and/or one or more targets ina target area and/or a detection area for ablation and/or furtherimaging and/or sensing, as appropriate.

In some embodiments, one or more bypass insert 216 is configured tonarrow, compress, constrict, and/or occlude at least part of the bypasslumen. In some embodiments, one or more bypass insert 216 is configuredto expand and/or enlarge at least part of the bypass lumen. Inillustrative embodiments, one or more bypass insert 216 is configuredincluding an expandable material configured to modulate the width of theinner circumference and/or diameter of the bypass lumen, optionallydecreasing the diameter and/or circumference as the material expands. Inillustrative embodiments, one or more bypass insert 216 is configured asa compression band that modulates the width of the bypass lumenoptionally from the exterior of the local bypass 210. For example, thecompression band is optionally configured with clamps and/or ratchetsdesigned to tighten (and/or to loosen) responsive to control circuitry.

In some embodiments, one or more bypass insert 216 is configured tomodulate at least part of the local bypass 210 at least partially basedon one or more images captured by one or more sensors 130. Inillustrative embodiments, one or more bypass inserts 216 constricts thebypass lumen trapping one or more targets for ablation, and/or one ormore possible targets from further sensing. In some embodiments one ormore bypass insert is configured to remotely, wirelessly and/orprogrammably modulate at least part of the bypass lumen. In illustrativeembodiments, one or more bypass inserts 216 occludes a portion of thebypass lumen based on remote instructions from one or more externalsources. In illustrative embodiments, one or more bypass inserts 216occludes a portion of the bypass lumen based on a programmable protocolfor sensing and ablation at predetermined intervals.

Embodiments of the extralumenal bypass 212 are optionally configured tofunction proximal to a blood vessel or lymph vessel lumen. Inillustrative embodiments, the extralumenal bypass 212 is configured as atubular structure optionally running parallel to the vessel andoptionally including porous material. In illustrative embodiments, theextralumenal bypass 212 is configured with an enlarged cavity optionallyincluding one or more sensors 130, one or more energy sources 110,and/or one or more power sources 160.

In some embodiments, the extralumenal bypass 212 is configured with oneor more vessel insertion units 214, optionally responsive to controlcircuitry 150. In illustrative embodiments, one or more vessel insertionunits 214 are configured to pierce the vessel wall to form an opening,optionally closable, through which fluid and/or cells may enter theextralumenal bypass 212, optionally by way of one or more valves 215. Inillustrative embodiments, fluid flow into the bypass lumen is a passiveprocess (e.g. the insertion sites are continually open), and/or anactive process (e.g. the insertion sites must be opened and/or closed byan active mechanism). In illustrative embodiments, fluid flow and/orcells are optionally sucked into the local bypass through the one ormore insertion units, and/or forced into the local bypass 210 throughthe insertion units. Mechanisms for providing suction and/or force areknow in the art and/or described herein.

In illustrative embodiments, there is at least one vessel insertion unit214 on each end of the extralumenal bypass 212, optionally configuredsuch that fluid flows in at one end and out at the other end. Inillustrative embodiments, the one or more vessel insertion units areconfigured such that fluid and/or cells enter the extralumenal bypass212 through the downflow (in reference to the fluid flow in the vessellumen) insertion site and exit the extralumenal bypass 212 through anupflow insertion site. Vessel insertion units 214 and methods forimplanting such devices are known to those of skill in the art and/orare described herein.

In illustrative embodiments, some configurations of the extralumenalbypass 212 reduce fluid flow velocity including, but not limited to,increased length compared to the distance between insertion locations,baffling of local bypass lumen, changes in direction of the local bypasslumen, enlargement of the local bypass lumen as compared with the vessellumen, and/or a path that is partly or completely opposite to the vesselfluid flow and/or gravity (e.g. fluid entry from the downflow insertionsite and return via the upflow insertion site).

In some embodiments, the one or more vessel insertion units 214 areconfigured to modulate fluid flow to, from, and/or within the localbypass lumen (e.g. optionally through one or more valves 215),optionally at least partially based on one or more image responsescaptured by the one or more sensors 130, and optionally responsive tocontrol circuitry 150. In illustrative embodiments, one or more valves215 in the one or more vessel insertion units 214 are configured tocontrol fluid flow (and/or cellular flow) into the local bypass lumen.The one or more valves are optionally configured to open responsive tocontrol circuitry 150 based at least partially on the analysis of one ormore image responses from one or more sensors 130 at least partiallyidentifying one or more possible targets and/or one or more targets.

In illustrative embodiments, one or more valves 215 in the one or morevessel insertion units 214 are configured to control fluid flow (and/orcellular flow) out the local bypass lumen. The one or more valves areoptionally configured to open responsive to control circuitry 150 basedat least partially on the analysis of one or more image responses fromone or more sensors 130 (optionally internal to the local bypass lumen)at least partially identifying one or more possible targets as not beingone or more targets. The one or more valves are optionally configured toopen responsive to control circuitry 150 following ablation (optionallywithin the local bypass lumen) of the one or more possible targetsand/or one or more targets.

In illustrative embodiments, one or more valves 215 in the one or morevessel insertion units 214 are configured to control fluid flow (and/orcellular flow) within the local bypass lumen. The one or more valves 215are optionally configured to open and/or close responsive to controlcircuitry 150 based at least partially on an analysis of the velocity ofmovement of one or more possible targets and/or one or more targets asthey traverse the local bypass lumen. In illustrative embodiments, theone or more valves 215 are optionally closed to reduce the velocity andoptionally one or more valves are opened to increase the velocity. Inillustrative embodiments, one or more valves 215 are located internal tothe local bypass lumen and are optionally configured to selectively stopfluid and/or cellular flow in one or more parts of the local bypasslumen. Selective modulation of fluid flow may be useful for enhancedimaging, functioning of one or more physiological sensors 140, and/orfor ablation, optionally targeted ablation, among other reasons.

In some embodiments, the one or more vessel insertion units 214 and/orthe one or more valves 215 are remotely controlled, wirelesslycontrolled, and/or programmable. In illustrative embodiments, the one ormore vessel insertion units 214 are configured for remote control,optionally by the subject, and/or a medical professional such that theextralumenal bypass 212 is connected to the vessel via the one or morevessel insertion units 214 optionally at an appropriate monitoring timeby the subject, and/or in the presence of a medical profession,optionally during a routine exam for example. In illustrativeembodiments, the one or more valves 215 are configured as part of theone or more insertion units and remotely controlled by one or moreexternal source, optionally the subject and/or a medical professional.

In illustrative embodiments, the one or more vessel insertion units 214and/or one or more valves 215 are optionally programmed to insert in tothe vessel wall and/or the one or more valves 215 to open and/or closeat pre-determined intervals. In illustrative embodiments, the one ormore vessel insertion units 214 and/or one or more valves 215 areoptionally programmed to insert in to the vessel wall and/or the one ormore valves 215 to open and/or close based at least partially on theoccurrence of some event, optionally a measurable event such as sensingof one or more possible targets by the one or more sensors 130 and/orone or more possible diseases and/or disorders optionally be one or morephysiological sensors 140.

Embodiments of the extralumenal bypass 212 are optionally configuredwith one or more vessel attachment unit 180. In some embodiments, theone or more vessel attachment unit 180 is configured to attach to theexternal vessel wall. In some embodiments, the one or more vesselattachment unit 180 is configured to at least partially surround anexternal circumference of a vessel. In some embodiments, the one or morevessel attachment unit 180 is configured as a mesh sleeve.

In illustrative embodiments, one or more vessel attachment unit 180 isconfigured to extend lengthwise down the extralumenal bypass 212 andconcurrently lengthwise down the exterior wall of the vessel. In someembodiments, the one or more vessel attachments unit 180 is configuredto attach responsive to control circuitry 150. In illustrativeembodiments, the one or more vessel attachment unit 180 is configured totighten and/or loosen based on control circuitry 150, optionallyremotely controlled and/or programmably controlled.

In illustrative embodiments, one or more vessel attachment unit 180 isconfigured as optionally a series of intermittent connections betweenthe extralumenal bypass 212 and the vessel wall. In illustrativeembodiments, one or more vessel attachment unit 180 is configured toattach each end of the extralumenal bypass 212 to the vessel wall. Inillustrative embodiments, one or more vessel attachment unit 180 isconfigured as part of and/or including the one or more vessel insertionunits 214. In illustrative embodiments, the one or more vesselattachment unit 180 is configured to wrap partially and/or completelyaround the external vessel wall. In illustrative embodiments, the one ormore vessel insertion units 214 are optionally configured toconcomitantly and/or automatically pierce the vessel wall (e.g. duringaffixation).

In some embodiments, the one or more vessel attachment unit 180 isconfigured to include one or more vessel anchors and/or vessel clamps.In illustrative embodiments, the one or more vessel anchors optionallyinclude one or more hooks and/or barbs optionally configured to catchinto the external wall of the lumen, optionally without piercing throughto the lumen. In illustrative embodiments, one or more vessel clamps areconfigured to connect part, or the entirety, of the vessel attachmentunit 180 around the vessel wall. In illustrative embodiments, the one ormore clamps are configured for optional tightening and/or loosening(e.g. for constricting and/or compressing the vessel lumen as well asattachment), optionally responsive to control circuitry 150. In someembodiments, one or more vessel clamps include one or more adhesives,optionally including geckel. Other mechanisms and devices for affixationand/or closure are known in the art and/or described herein.

In some embodiments, one or more vessel attachment unit 180 isconfigured to include one or more sensors 130 and/or one or more energysources 110, optionally configured to align cooperatively duringaffixation of the vessel attachment unit 180 to the vessel wall. In someembodiments, one or more vessel attachment unit 180 is configured toinclude one or more energy sources 110, optionally configured to alignto a target area during affixation of the vessel attachment unit 180 tothe vessel wall.

In some embodiments, the extralumenal bypass 212 is configured with oneor more bypass insert 216 responsive to control circuitry and configuredto modulate at least part of the bypass lumen as described herein; thoseembodiments are also encompassed for the bypass insert 216 associatedwith the intralumenal bypass 211 unless context dictates otherwise.

Embodiments of the intralumenal bypass 211 are optionally configured tofunction in a blood vessel or lymph vessel lumen. In illustrativeembodiments, an intralumenal bypass 211 is a roughly tubular shape sizedfor use within a vessel lumen, and optionally including mesh to allowpassage of fluid while retaining cells, etc. In illustrativeembodiments, an intralumenal bypass 211 is a roughly oblong shape sizedfor use within a vessel lumen, configured such that the length dimensionis parallel to the length dimension of the vessel lumen, and optionallyopen at both ends (e.g. upflow and downflow). In illustrativeembodiments, the intralumenal bypass 211 is configured from opticallypure material optionally designed to enhance imaging and/or sensing. Inillustrative embodiments, one or more intralumenal bypass 211 isconfigured such that ablation energy does not significantly penetratethe lumen wall.

In some embodiments, the intralumenal bypass 211 is configured with oneor more vessel lumen anchors 190. In illustrative embodiments, one ormore vessel lumen anchors 190, optionally hooks, are configured to affixthe intralumenal bypass 211 to the internal wall of the vessel lumen. Insome embodiments one or more vessel lumen anchors 190 are expandablebraces that contact the lumen walls in opposition. In some embodiments,a combination of anchors may be used, for example, braces at one or moreopening of the intralumenal bypass 211, and hooks along the exteriorbypass wall. In illustrative embodiments, the intralumenal bypass 211 isaffixed using geckel.

In some embodiments, the one or more vessel lumen anchors 190 areconfigured to attach to the vessel lumen responsive to control circuitry150. In illustrative embodiments, the intralumenal bypass 211 isoptionally configured to be placed in a vessel lumen using some form ofmicrosurgery, optionally an endoscopic approach, where the vessel lumenanchors 190 are triggered to attach to the lumen wall remotely,wirelessly, and/or programmably. In illustrative embodiments, the vessellumen anchors 190 can by controllably released to facilitate removaland/or repositioning of the intralumenal bypass 211.

In some embodiments, the intralumenal bypass 211 is configured with atleast one closable opening 213 on an upflow end and/or downflow end ofthe intralumenal bypass 211. In some embodiments, the one or moreclosable openings 213 (e.g. one or more valves 215) are responsive tocontrol circuitry 150 and are configured to modulate fluid flow toand/or from the local bypass lumen. In illustrative embodiments, theintralumenal bypass 211 is configured with closable openings 213configured to allow fluid flow to enter one end, traverse the bypasslumen and exit another end. In illustrative embodiments, the closableopenings 213 open and close based on a pre-programmed pattern,optionally to allow random sampling of cells in the fluid flow, andoptionally the bypass lumen is configured to include one or more sensors130 and/or energy sources 110.

In illustrative embodiments, the closable openings 213 open and closeresponsive to control circuitry 150 at least partially based on imageresponses captured by sensors 130 associated with one or more possibletargets. For example, one or more sensors 130 and energy sources 110 areoptionally cooperatively positioned upflow from the intralumenal bypass211, and following analysis of one or more image responses by controlcircuitry 150 indicating the presence of one or more possible targets,one or more valves 215 in the upflow closable opening 213 open inresponse to the control circuitry 150 to allow entry of the one or morepossible targets. One or more valves 215 in the downflow closableopening 213 optionally also sequentially close responsive to controlcircuitry 150 to temporarily trap the one or more possible targets inthe bypass lumen. Optionally, additional image responses may be capturedby the one or more sensors 130 (optionally different types or quality ofsensors) and analyzed to determine whether the one or more possibletargets are one or more targets. Optionally, ablation energy is providedto the bypass lumen to ablate the one or more possible targets and/orthe one or more targets optionally in a target area.

In some embodiments, the extraluminal bypass 212 is configured with oneor more bypass insert 216 responsive to control circuitry and configuredto modulate at least part of the bypass lumen as described herein; thoseembodiments are also encompassed for the bypass insert 216 associatedwith the intralumenal bypass 211 unless context dictates otherwise.

Embodiments of one or more devices 300 include one or more reservoirs310 (see e.g., FIG. 9 and FIG. 10) configured to receive one or moretargets from, and to function in, or proximal to, one or more bloodvessel or lymph vessel. In some embodiments, at least one location inthe reservoir lumen has a circumference and/or diameter such that one ormore cells traverse the location in single file and/or traverse alocalized region, optionally to facilitate sensing and/or ablation ofone or more possible targets and/or one or more targets. In illustrativeembodiments, the constriction in the reservoir lumen is such that cellslarger than a certain size cannot pass (e.g. cells larger than normallymph cells and/or cells larger than normal constituents of the blood).In illustrative embodiments, the constriction in the reservoir lumen issuch that all cells can pass, but optionally at a restricted velocitydepending on size (e.g. cell deformation is required to allow passage oflarger cells).

In some embodiments, one or more reservoirs 310 are configured tofunction in a vessel lumen (e.g. intralumenal reservoir 311), andoptionally configured with one or more vessel lumen anchors 190, one ormore self-sealing apertures 313, and/or one or more closable openings213 optionally including one or more valves 215. In some embodiments,one or more reservoirs 310 are configured to function proximal to avessel (e.g. extralumenal reservoir 312), and optionally configured withone or more vessel insertion units 214 (optionally including one or morevalves 215), one or more vessel attachment units 180, and/or one or moreself-sealing apertures 313.

In some embodiments, one or more sensor 130 and/or one or more controlcircuitry 150 (and optionally components such as, but not limited to,one or more energy source 110, one or more power source 160, and/or oneor more local bypass 210) are separate from and/or external to the oneor more reservoirs 310. In some embodiments, one or more sensor 130and/or one or more control circuitry 150 (and optionally components suchas but not limited to one or more energy source 110, one or more powersource 160, and/or one or more local bypass 210) are part of, orinternal to, the one or more reservoirs 310. In some embodiments, thereare one or more sensors 130 and/or one or more control circuitry 150(and optionally components such as but not limited to one or more energysource 110, one or more power source 160, and/or one or more localbypass 210) external to the one or more reservoirs 310 as well asinternal to the one or more reservoirs 310. Embodiments in which one ormore parts of the device 300 are not attached and/or internal to the oneor more reservoirs 310, may also include one or more of one or moreinsert 170, one or more vessel attachment units 180, and/or one or morevessel lumen anchors 190.

Embodiments of the one or more reservoirs 310 are optionally configuredwith one or more reservoir inserts responsive to control circuitry 150,and configured to modulate at least part of a reservoir lumen,optionally at least part of the inner (e.g. interior) and/or outer (e.g.exterior) circumference and/or diameter of the lumen. Embodimentsdiscussed in relation to the insert 170 and/or bypass insert 216 herein,are also applicable to the reservoir insert, unless context dictatesotherwise.

Embodiments of the one or more reservoirs 310 are optionally configuredwith one or more closable openings 213 configured such that one or moreof the one or more closable openings are externally accessible followingimplantation in the subject. In illustrative embodiments, the one ormore reservoirs 310 are configured to be accessed externally, optionallyby the subject and/or by a medical professional. In illustrativeembodiments, the one or more reservoir 310 is accessible via a largebore needle and/or via a portal configured for placement such thataccess is close to the skin surface and/or the portal is able to bepalpated to determine the entry point. In illustrative embodiments, thelocation of the access portal may be identified through X-raytechnology, MRI, imaging, or other methods known in the art. Inillustrative embodiments, the one or more reservoir 310 is accessiblevia microsurgery, optionally through endoscopy or other appropriatemedical procedure. Methods of access are known to those of skill in theart.

In some embodiments, one or more of the one or more closable openings213 and/or valves 215 are self-sealing (e.g. self-sealing aperture 313).In illustrative embodiments, one or more reservoir 310 is configuredwith a self-sealing aperture 313 optionally positioned to be accessibleexternally following placement in a subject. Self-sealing apertures 313are known in the art, for example as used as part of the multiple useseal for dispensing fluid pharmaceuticals from a vial. Self-sealingapertures 313 are optionally configured to allow penetration of a needle(e.g. a syringe needle and/or biopsy needle), withdrawal of part or allof the contents of the reservoir 310 and/or one or more compartments ofthe reservoir, and then to reseal (e.g. such that cells and/or fluidcannot escape) following withdrawal of the needle from the aperture.

Embodiments of one or more device 300 my optionally include one or morelocal bypass 210. For example, although embodiments of the one or moredevice 300 are described as they relate to one or more blood vesseland/or lymph vessel, these embodiments are also applicable to the one ormore device 300 in association with the local bypass 210, unless contextdictates otherwise. In some embodiments, the one or more reservoir 310is configured as an integral part of one or more local bypass 210,optionally intralumenal or extralumenal. In some embodiments, the one ormore reservoir 310 is configured as an additional part of the localbypass 210, optionally attachable externally and/or internally. In someembodiments, the one or more reservoir 310 is configured as part of asystem including the one or more local bypass 210.

In illustrative embodiments, the local bypass 210 is configured toreceive fluid flow from a vessel lumen, which fluid passes through asensing system (optionally including one or more energy source 110, oneor more sensors 130, one or more control circuitry 150, and/or one ormore bypass insert 216) configured to identify one or more targetsand/or possible targets, and then to one or more reservoirs or reservoircompartments optionally through one or more closable openings 213 and/orvalves 215.

Embodiments of the one or more reservoirs 310 are optionally configuredwith one or more compartments within the one or more reservoirs 310. Insome embodiments, one or more reservoir inserts optionally including oneor more valves 215 direct fluid and/or cellular flow to one or more ofthe compartments optionally based on control circuitry 150. Inillustrative embodiments, one or more targets and/or one or morepossible targets are directed to different compartment at leastpartially based on space availability and/or at least partially based onthe time of collection, for example. In some embodiments, one or morereservoir inserts, optionally including one or more valves 215, directfluid and/or cellular flow to one or more of the compartments optionallyat least partially based on analysis by control circuitry 150 of one ormore image responses captured by one or more sensors 130.

In illustrative embodiments, one or more possible targets and/or one ormore targets are segregated into one or more different compartmentsdepending on one or more criteria, optionally disease and/or disorderassociated criteria. For example, putatively cancerous cells may bedirected to one compartment and putatively infectious agents may bedirected to another compartment. The one or more compartments may beconfigured for additional analysis of the one or more putative targetsby one or more sensing systems (optionally including one or more energysources 110, one or more sensors 130 and one or more control circuitry150).

Embodiments of the extralumenal reservoir 312 are optionally configuredto function proximal to a blood vessel and/or lymph vessel lumen. Inillustrative embodiments, the extralumenal reservoir 312 is configuredas a roughly bag-like structure, optionally including porous and/ormesh-like material. In illustrative embodiments, the extralumenalreservoir 312 is configured as an expandable structure, optionallyincluding a reservoir relief valve (e.g. purge valve) optionallyconfigured for releasing excess pressure, and/or fluid (optionallycellular) flow, optionally following at least partial ablation and/ormodification of one or more targets and/or possible targets. Inillustrative embodiments, at least part of the reservoir is configuredfor enhanced imaging and/or sensing. In illustrative embodiments, atleast part of the reservoir is configured for ablation, optionally withlimited collateral damage to surrounding subject tissues. Inillustrative embodiments, the extralumenal reservoir 312 is configuredwith one or more cavity optionally including one or more sensors 130,one or more energy sources 110, one or more reservoir inserts, and/orone or more power sources 160.

In some embodiments, the extralumenal reservoir 312 is configured withone or more vessel insertion units 214, optionally responsive to controlcircuitry 150. Embodiments of the one or more vessel insertion units 214discussed in relation to the extralumenal bypass 212 herein, are alsoapplicable to the extralumenal reservoir 312, unless context dictatesotherwise.

In illustrative embodiments, one or more extralumenal reservoirs 312 areconfigured with one vessel insertion unit 214 configured such that fluid(and/or cells) from a vessel lumen flow in to the one or moreextralumenal reservoirs 312. In some embodiments, the one or more vesselinsertion units 214 are configured to modulate fluid flow to, from,and/or within the reservoir lumen (e.g. optionally through one or morevalves 215), optionally at least partially based on one or more imageresponses captured by the one or more sensors 130, and optionallyresponsive to control circuitry 150.

In illustrative embodiments, one or more valves 215 in the one or morevessel insertion units 214 are configured to control fluid flow (and/orcellular flow) into the reservoir lumen. The one or more valves areoptionally configured to open responsive to control circuitry 150 basedat least partially on the analysis of one or more image responses fromsensing systems (optionally including one or more sensors 130, one ormore coordinating energy sources 110, and one or more control circuitry150), and optionally external to the extralumenal reservoir 312 and/orconfigured to image the vessel lumen) at least partially identifying oneor more possible targets and/or one or more targets.

In illustrative embodiments, the one or more vessel insertion units 214and/or valves 215 are configured to be programmable, optionally remotelyand/or wirelessly, optionally to screen for the presence and/or absenceof one or more targets, and/or to count numbers of one or more targets.In illustrative embodiments, the one or more sensing systems areconfigured remotely (by the subject and/or a medical professional) todetect image responses associated with one or more diseases or disordersfor which the subject is considered at risk (e.g. due to genetics,health care, lifestyle, and/or symptoms) and to trigger the one or morevalves 215 to open in the presence of one or more possible targets,and/or to open at designated sensing times (e.g. hourly, 2× per day, 4×per day, daily, weekly, monthly, etc.).

Embodiments of the extralumenal reservoir 312 are optionally configuredwith one or more vessel attachment unit 180. Embodiments of the one ormore vessel attachment units 180 discussed herein, optionally inrelation to the extralumenal bypass 212, are also applicable to theextralumenal reservoir 312, unless context dictates otherwise.

Embodiments of the extralumenal reservoir 312 are optionally configuredwith one or more reservoir insert responsive to control circuitry andconfigured to modulate at least part of the reservoir lumen. Embodimentsof the one or more inserts 170 and/or one or more bypass inserts 216discussed herein, are also applicable to one or more reservoir insertsin the extralumenal reservoir 312, unless context dictates otherwise.

Embodiments of the intralumenal reservoir 311 are optionally configuredto function in a blood vessel or lymph vessel lumen. In illustrativeembodiments, an intralumenal reservoir 311 is a roughly tubular shapesized for use within a vessel lumen, and optionally including mesh toallow passage of fluid while retaining cells, etc. In illustrativeembodiments, an intralumenal reservoir 311 is a roughly oblong shapesized for use within a vessel lumen, configured such that the lengthdimension is parallel to the length dimension of the vessel lumen, andoptionally includes one or more relief valve (e.g. pressure relief valveand/or fluid (cellular) flow release valve, optionally followingablation). In illustrative embodiments, the intralumenal reservoir isconfigured for enhanced sensing and/or imaging, and is designed toquantify numbers of targets, and/or percentages of targets based oncontrol circuitry.

In some embodiments, the intralumenal reservoir 311 is configured withone or more vessel lumen anchors 190 optionally associated with one ormore vessel insertion units 214 and/or one or more sensing systems.Embodiments of the one or more vessel lumen anchors 190 discussed hereinare also applicable to one or more intralumenal reservoirs 311, unlesscontext dictates otherwise.

Embodiments of the intralumenal reservoir 311 are configured with atleast one closable opening 213 and/or one or more valves 215 providing aconduit from the vessel lumen to the reservoir lumen. In someembodiments, one or more closable opening is configured to be located onan upflow part of the reservoir 310. In some embodiments, one or moreclosable opening is configured to be located on a downflow part of thereservoir 310. Embodiments of the one or more closable opening 213and/or one or more valves 215 discussed herein are also applicable toone or more intralumenal reservoirs 311, unless context dictatesotherwise.

In illustrative embodiments, the intralumenal reservoir 311 isconfigured with closable openings 213 configured to allow fluid flow oroptionally cellular flow to enter, optionally flow pass one or moresensing systems, and then enter one or more reservoir compartmentsoptionally for storage, be ablated, and/or pass through another closableopening back into the subject. In illustrative embodiments, the closableopenings 213 open and close to selectively receive and/or contain one ormore identified targets.

In some embodiments, the intraluminal reservoir 311 is configured withone or more reservoir insert responsive to control circuitry andconfigured to modulate at least part of the reservoir lumen. Embodimentsdescribed for one or more insert 170 and/or one or more bypass insert216 also encompassed for the reservoir insert associated with theintralumenal reservoir 311, unless context dictates otherwise.

It is contemplated that components, such as energy sources 110, sensors130, control circuitry 150, and/or power sources 160, for example, willoptionally be attached, connected to, place within, manufactured on orin, and/or formed integrally with one or more structural element.Methods for manufacture and/or assembly are known in the art and/ordescribed herein.

Embodiments of one or more device 100, 200, and/or 300 may include oneor more energy sources 110 (see e.g. FIG. 2 and FIG. 3). In someembodiments, one or more device 100 may include a first energy sourceconfigured to function in, or proximal to, one or more blood vessel orlymph vessel, and to provide energy configured to elicit one or moreimage responses associated with one or more blood vessel or lymphvessel; and one or more second energy source responsive to controlcircuitry and configured to provide ablation energy to a target areaduring the expected transit time of one or more targets through thetarget area.

In some embodiments, one or more device 200 may optionally include afirst energy source configured to function in, or proximal to, a localbypass lumen, and to provide energy configured to elicit one or moreimage responses associated with a local bypass lumen; and optionally oneor more second energy source responsive to control circuitry andconfigured to provide ablation energy to a target area during theexpected transit time of one or more targets through the target area. Insome embodiments, the first energy source 110 is configured to provideenergy to elicit one or more image responses associated with fluid(and/or cellular) flow in, or proximal to (optionally upflow and/ordownflow), the local bypass 210. In some embodiments, the first energysource 110 is configured to provide energy to elicit one or more imageresponses associated with fluid flow in the local bypass lumen. In someembodiments, the second energy source 110 is configured to emit ablationenergy within, or proximal to, the local bypass 210, optionally with thelocal bypass lumen.

In some embodiments, one or more device 300 may include a first energysource configured to function in, or proximal to, one or morereservoirs, and to provide energy configured to elicit one or more imageresponses associated with the one or more reservoirs; and optionally oneor more second energy source responsive to control circuitry andconfigured to provide ablation energy to a target area during theexpected transit time of one or more targets through the target area. Insome embodiments, the first energy source 110 is configured to provideenergy to elicit one or more image responses associated with fluid(and/or cellular) flow in, or proximal to (optionally upflow and/ordownflow), the one or more reservoirs 310. In some embodiments, thefirst energy source 110 is configured to provide energy to elicit one ormore image responses associated with fluid flow in the lumen of the oneor more reservoirs 310. In some embodiments, the second energy source110 is configured to emit ablation energy within, or proximal to, theone or more reservoirs 310, optionally within the lumen of the one ormore reservoirs. In some embodiments, the target area is in the lumen ofa blood and/or lymph vessel, upflow and/or downflow of one or morereservoirs, and/or in the reservoir lumen.

One or more energy sources 110 may include, but are not limited to, oneor more electromagnetic energy sources 111, one or more acoustic energysources 120 (e.g. one or more ultrasonic energy sources 121), and/or oneor more charged particle energy sources 125. One or more electromagneticenergy sources 111 may include, but are not limited to, one or moreoptical energy sources 112, one or more radio frequency sources 113, oneor more magnetic energy sources 114, one or more thermal energy sources115, and/or one or more X-ray energy sources 116. One or more opticalenergy sources 112 may include, but are not limited to, one or morevisual energy sources 117, infrared energy sources 118, and/or one ormore ultraviolet energy sources 119. In some embodiments, one or moreenergy sources described herein and/or known in the art may bespecifically excluded, e.g. one or more electromagnetic energy sourcenot including one or more X-ray energy source. In some embodiments oneor more electromagnetic energy source 111 is one or more laser. In someembodiments, the optical energy is provided through fiber optic linesand/or a web of fiber optic lines. In some embodiments, one or moreenergy sources 110 are programmable, remote-controlled, wirelesslycontrolled, and or feedback-controlled.

One or more energy sources 110 (e.g. electromagnetic 111 and/or acoustic120) are configured to elicit one or more image responses such as, butnot limited to, electromagnetic image responses including, but notlimited to, optical image responses (e.g. visible light image responses,infrared image responses, ultraviolet image responses, and/orfluorescent image responses, among others), radiofrequency imageresponses, and/or magnetic image responses. One or more energy sources110 are configured to elicit one or more image responses including ascattering response and/or an absorptive response from the one or moretargets. One or more image responses may include, but are not limitedto, acoustic image responses, such as, but not limited to, ultrasonicimage responses. One or more image responses may include, but are notlimited to, thermal image responses, and/or color image responses. Oneor more image responses may include, but are not limited to, lightscatter and/or light absorption. Characteristics of the energyappropriate for generating one or more image responses are known in theart and/or described herein.

One or more energy sources 110 (e.g. electromagnetic 111, acoustic 120and/or particle beam 125) are configured to provide ablation energy toone or more targets or to a target area. In some embodiments, theelectromagnetic energy source is an optical energy source and/or anX-ray energy source. In some embodiments, the electromagnetic energy isprovided by one or more lasers. In some embodiments, one or more energysource 110 is configured to function within the one or more blood vesseland/or lymph vessel. In some embodiments, one or more energy source 110is configured to function proximal to the one or more blood vesseland/or lymph vessel.

In some embodiments, different energy sources 110 provide energy toelicit an image response and to ablate one or more targets. In someembodiments, one energy source 110 provides energy to elicit an imageresponse and to ablate one or more targets. In some embodiments, morethan one energy source 110 provides energy to elicit an image response.In some embodiments, more than one energy source provides energy toablate one or more targets. In some embodiments, a first energy sourceand a second energy source are the same energy source. In someembodiments, one or more of the one or more second energy source isseparate from the one or more first energy source and/or the one or moresensors.

As used herein, the term “electromagnetic energy” may include, but isnot limited to, radio waves, microwaves, terahertz radiation, infraredradiation, visible light, X-rays, and gamma rays. In some embodiments,one or more of these frequencies may be explicitly excluded from thegeneral category of electromagnetic energy (e.g. electromagnetic energysources, but not including X-ray energy sources). Electromagnetic energy(or radiation) with a wavelength between approximately 400 nm and 700 nmis detected by the human eye and perceived as visible light. Opticallight may also include near infrared (longer than 700 nm) andultraviolet (shorter than 400 nm).

As used herein, the term “charged particle” may include particlesgenerated using one or more particle beams. A particle beam isoptionally an accelerated stream of charged particles or atoms that maybe directed by magnets and focused by electrostatic lenses, althoughthey may also be self-focusing. Particle beams may be high energy beams(e.g. created in particle accelerators), medium and/or low energy beams.

Electromagnetic or optical energy is made up of photons. Electromagneticenergy includes, but is not limited to, single photon electromagneticenergy, two photon electromagnetic energy, multiple wavelengthelectromagnetic energy, and extended-spectrum electromagnetic energy.Electromagnetic energy may be used for eliciting image responses and/orfor ablation of one or more targets.

As used herein, the term “fluorescence” may include the production oflight (emission) following excitation by electromagnetic energy.Fluorescence may result from an inherent response of one or more targetsto excitation with electromagnetic energy. As used herein, the term“auto-fluorescence” may include an inherent fluorescent response fromone or more targets.

Electromagnetic energy sources 111 may be configured to emit energy as acontinuous beam or as a train of short pulses. In the continuous wavemode of operation, the output is relatively consistent with respect totime. In the pulsed mode of operation, the output varies with respect totime, optionally having alternating ‘on’ and ‘off’ periods. Inillustrative examples, one or more energy sources are configured to emitpulsed energy to specifically ablate a limited area and/or a limitednumber of target cells. In illustrative examples, one or more energysources are configured to emit continuous energy to excite endogenousfluorophores to emit fluorescence.

One or more electromagnetic energy sources 111 may include one or morelasers having one or more of a continuous or pulsed mode of action. Oneor more pulsed lasers may include, but are not limited to, Q-switchedlasers, mode locking lasers, and pulsed-pumping lasers. Mode lockedlasers emit extremely short pulses on the order of tens of picosecondsdown to less than 10 femtoseconds, the pulses optionally separated bythe time that a pulse takes to complete one round trip in the resonatorcavity. Due to the Fourier limit, a pulse of such short temporal lengthmay have a spectrum which contains a wide range of wavelengths.

In some embodiments, the energy (optionally electromagnetic) is focusedat a depth of approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, or 3.0 mm within a vessellumen, a bypass lumen, and/or a reservoir. In some embodiments, theelectromagnetic energy is focused at a depth of approximately 0.1 to 3mm, 0.1 to 2.5 mm, 0.1 to 2.0 mm, 0.1 to 1.5 mm, 0.1 to 1.0 mm, 0.1 to0.5 mm, 0.5 to 3.0 mm, 0.5 to 2.5 mm, 0.5 to 2.0 mm, 0.5 to 1.5 mm, 0.5to 1.0 mm, 1.0 to 3.0 mm, 1.0 to 2.5 mm, 1.0 to 2.0 mm, 1.0 to 1.5 mm,1.5 to 3.0 mm, 1.5 to 2.5 mm, 1.5 to 2.0 mm, 2.0 to 3.0 mm, 2.0 to 2.5mm, or 2.5 to 3.0 mm within a vessel lumen, a bypass lumen, and/or areservoir.

In some embodiments, the electromagnetic energy is generated by twophotons having the same wavelength. In some embodiments, theelectromagnetic energy is generated by two photons having a differentwavelength. Electromagnetic energy generated by two photons isoptionally focused at a depth within a vessel lumen, a bypass lumen,and/or a reservoir, optionally at one or more depths as described aboveand/or herein.

As used herein, the term “two-photon” may include excitation of afluorophore by two photons in a quantum event, resulting in the emissionof a fluorescence photon, optionally at a higher energy than either ofthe two excitatory photons, optionally using a femtosecond laser. Insome embodiments, two photon electromagnetic energy is coupled through avirtual energy level and/or coupled through an intermediate energylevel.

As used herein, the term “extended-spectrum” may include a range ofpossible electromagnetic radiation wavelengths within the full spectrumof possible wavelengths, optionally from extremely long to extremelyshort. One of skill in the art is able to select appropriate ranges forthe devices and methods disclosed herein based on information publiclyavailable and/or disclosed herein.

In some embodiments, the energy (optionally electromagnetic) may bedefined spatially and/or directionally. In some embodiments, theelectromagnetic energy may be spatially limited, optionally spatiallyfocused and/or spatially collimated. In illustrative embodiments, theelectromagnetic energy optionally contacts less than less than an entirepossible area, or an entire possible target, and/or is limited to acertain depth within a vessel lumen, a bypass lumen, and/or a reservoir.

In some embodiments, the energy (optionally electromagnetic) may bedirectionally limited, directionally varied, and/or directionallyvariable. In illustrative embodiments, the energy may be provided onlyin a single direction, for example 90 degrees from the horizontal axisof a device, or toward a lumen wall, a bypass wall, and/or a reservoirwall. In illustrative embodiments, the energy may be provided over arange of directions for example, through movement of the energy source110, through movement of the entire device, and/or through illuminationfrom a variety of energy sources 110 in the device.

Electromagnetic energy and/or acoustic energy configured to induce animage response in a target may be selected, optionally manually,remotely, programmably, wirelessly, and/or using feedback information.Frequencies that induce an image response in one or more targets areknown in the art and/or discussed herein. In some embodiments, selectionof excitation energy may be performed in advance, or as a result ofinformation received, optionally including feedback information,optionally from one or more sensors 130 or provided by one or moreexternal sources.

Electromagnetic energy, acoustic energy, and/or particle beam energyconfigured to ablate one or more targets may be selected, optionallymanually, remotely, programmably, wirelessly, and/or using feedbackinformation. Frequencies useful to at least partially ablate one or moretargets are known in the art and/or discussed herein. In someembodiments, selection of ablation energy may be performed in advance,or as a result of information received, optionally including feedbackinformation, optionally from one or more sensors 130 or provided by oneor more external sources.

In addition to electromagnetic energy described herein, the ablationenergy may be supplied by energetic charged particles, such aselectrons, protons, or other ions. In one embodiment, the chargedparticles are directed towards the one or more targets and/or targetarea in the form of particle beams. In another embodiment, the chargedparticles are emitted over relatively wide solid-angles, and address thedesignated autofluorescent target by virtue of spatial proximity.

In one embodiment, particle beams are generated outside the body by beamgenerators such as particle accelerators, cathode ray tubes,electrostatic accelerators, voltage-multiplier accelerators,Cockcroft-Walton accelerators, Van de Graaff accelerators, Alvarezaccelerators, linear accelerators, circular accelerators, wakefieldaccelerators, collimated radioactive emitters, etc. The beams from thesesources can be directed towards the one or more targets and/or targetarea by mechanical, electrical, or magnetic methods. In someembodiments, the particle beams may be generated and directed fromlocations separate from the energy source 110 used to induce the imageresponse. In other embodiments, the particle beam may be generated inproximity to the energy source for eliciting the image response, byusing compact particle sources such as electrostatic accelerators,Alvarez accelerators, linear accelerators, voltage-multiplieraccelerators, Cockcroft-Walton accelerators, wakefield accelerators,collimated radioactive emitters, etc.

In some embodiments, particle beams are generated and delivered frominside the body. Compact particle beam generators such as electrostaticaccelerators, Alvarez accelerators, linear accelerators,voltage-multiplier accelerators, Cockcroft-Walton accelerators, orwakefield accelerators can be used. In one embodiment of avoltage-multiplier accelerator, the staged voltage elements can usehigh-field-strength capacitors. In another embodiment, the stagedvoltages can be generated in an array of photocells by photogenerationusing on-board or off-board light sources. In another embodiment of anin-vivo particle source, a radioactive emitter can be used to provide acharged particle source. One example of such a source is the Beta-Cath™System, developed by Novoste Corp.

In one embodiment, in-vivo radioactive sources can be encapsulatedwithin shielding which can be used to control charged particle exposureto nearby tissue. The shielding can have one or more portals, allowingfor collimated emission. The shielding can be movable, either across allor part of its extent, or across one or more portal openings, in orderto provide switchable particle sources. Shielding can be controllablymoved by mechanical techniques such as valves, shutters, or similardevices, can utilize movable liquids, such as Hg, or utilize othermethods. The particles from these in-vivo sources can be directedtowards the one or more targets and/or target area by mechanical,electrical, or magnetic methods, or may rely upon proximity.

Embodiments of one or more devices 100, 200, and/or 300 include one ormore sensors 130 (see, e.g., FIG. 4 and FIG. 5). In some embodiments,one or more sensors 130 are the same sensor. In some embodiments, one ormore sensors 130 are different sensors. In some embodiments, one or moresensors are in the same unit and/or are physically connected. In someembodiments, one or more sensors 130 are in separate units and/or notphysically connected. In some embodiments, one or more sensors 130 arein the same and/or different units than one or more energy sources 110.In some embodiments, the one or more sensors 130 are configured to alignwith the one or more energy sources 110 and cooperatively elicit andcapture image responses. In some embodiments, the one or more sensors130 are configured to orient to the one or more energy sources 110 tocooperatively elicit and capture image responses. One or more sensors130 may include, but are not limited to, one or more imaging sensors 131and/or one or more physiological sensors 140.

Embodiments of one or more device 200 include one or more sensors 130configured to function in, or proximal to, a local bypass 210,optionally the local bypass lumen. In some embodiments, the one or moresensors 130 are configured to capture one or more image responsesassociated with fluid (and/or cellular) flow in, or proximal to(optionally upflow and/or downflow), the local bypass 210. In someembodiments, the one or more sensors 130 are configured to capture oneor more image responses associated with fluid (and/or cellular) flow inthe local bypass lumen.

Embodiments of one or more devices 100, 200, and/or 300 include morethen one sensor 130, optionally several sensors of the same or differenttypes, optionally configured to function independently and/or insequentially. In illustrative examples, one or more device 200 includesone or more sensors 130 upflow (e.g. in the vessel lumen) from the localbypass 210 (optionally configured to identify one or more possibletargets for entry into the local bypass 210), one or more sensors withinthe local bypass lumen optionally configured to further image the one ormore possible targets, one or more sensors 130 configured to captureimages associated with ablation energy and modification of the one ormore possible targets and/or one or more targets, and/or one or moresensors 130 downflow (e.g. configured to image the fluid flowre-entering the vessel lumen) from the local bypass 210.

In illustrative examples, one or more device 300 includes one or moresensors 130 upflow (e.g. in the vessel lumen) from the reservoir 310(optionally configured to identify one or more possible targets forentry into the reservoir 310), one or more sensors within the reservoirlumen optionally configured to further image the one or more possibletargets, one or more sensors 130 configured to capture images associatedwith ablation energy and modification of the one or more possibletargets and/or one or more targets, and/or one or more sensors 130downflow (e.g. configured to image the fluid flow re-entering the vessellumen) from the reservoir 310. In some embodiments, the detection areais in the one or more reservoirs 310, upflow and/or downflow from theone or more reservoirs 310, proximal to the one or more reservoirs 310,proximal to the one or more blood and/or lymph vessels, and/or in avessel lumen.

One or more imaging sensors 131 may include, but are not limited to, oneor more electromagnetic energy sensors 132 and/or one or more acousticsensors 133 (e.g. ultrasonic sensors 134). One or more electromagneticenergy sensors 132 may include, but are not limited to, one or morephotodetectors 135, one or more radiofrequency antennae 136, one or moremagnetic energy sensors 137, one or more thermal sensors 138, and/or oneor more electrical energy sensors 139. One or more electromagneticenergy sensors 132 may include one or more optical sensors such as, butnot limited to, sensors configured to detect near IR, UV, fluorescence,and/or visual light.

One or more imaging sensors may include, but are not limited to,charge-coupled device cameras and/or complementary metal oxidesemiconductor (CMOS) cameras. One or more imaging sensors may include,but are not limited to, one or more piezo transducers, one or more MEMSdevices, one or more cavity resonators, one or more magneto resistivesensors, one or more magnetic field sensors, and/or one or more thermalsensors.

One or more physiological sensors 140 may include, but are not limitedto, one or more chemical and/or biological molecule sensors 141 (e.g.blood chemistry, chemical concentration, biosensors), one or more pHsensors 142, one or more time sensors 143 (e.g. timers, clocks), and/orone or more temperature sensors 144. One or more physiological detectors140 may include, but are not limited to blood pressure detectors, pulsedetectors, peristaltic action sensors, pressure sensors, flow sensors,viscosity sensors, and/or shear sensors.

One or more sensors may be configured to measure various parameters,including, but not limited to, the electrical resistivity of the fluid,the density or sound speed of the fluid, the pH, the osmolality, or theindex of refraction of the fluid at least one wavelength. The selectionof a suitable sensor for a particular application or use site isconsidered to be within the capability of a person having skill in theart. One or more of these and/or other sensing capabilities may bepresent in a single sensor or an array of sensors; sensing capabilitiesare not limited to a particular number or type of sensors.

One or more biosensors may detect materials including, but not limitedto, a biological marker, an antibody, an antigen, a peptide, apolypeptide, a protein, a complex, a nucleic acid, a cell (and, in somecases, a cell of a particular type, e.g. by methods used in flowcytometry), a cellular component, an organelle, a gamete, a pathogen, alipid, a lipoprotein, an alcohol, an acid, an ion, an immunomodulator, asterol, a carbohydrate, a polysaccharide, a glycoprotein, a metal, anelectrolyte, a metabolite, an organic compound, an organophosphate, adrug, a therapeutic, a gas, a pollutant, or a tag. A biosensor mayinclude an antibody or other binding molecule such as a receptor orligand.

One or more sensors optionally include, in part or whole, a gas sensorsuch as an acoustic wave, chemiresistant, or piezoelectric sensors, oran electronic nose. One or more sensors are optionally small in size,for example a sensor or array that is a chemical sensor (Snow (2005)Science 307:1942-1945), a gas sensor (Hagleitner, et al. (2001) Nature414:293-296.), an electronic nose, and/or a nuclear magnetic resonanceimager (Yusa (2005), Nature 434:1001-1005). Further examples of sensorsare provided in The Biomedical Engineering Handbook, Second Edition,Volume I, J. D. Bronzino, Ed., Copyright 2000, CRC Press LLC, pp.V-1-51-9, and U.S. Pat. No. 6,802,811) and/or known in the art.

In some embodiments, one or more sensors 130 are configured to captureone or more image responses including, but not limited to,electromagnetic image responses including, but not limited to, opticalimage responses (e.g. visible light image responses, infrared imageresponses, ultraviolet image responses, and/or fluorescent imageresponses, among others), radiofrequency image responses, and/ormagnetic image responses. One or more image responses may include, butare not limited to, acoustic image responses, such as, but not limitedto, ultrasonic image responses. One or more image responses may include,but are not limited to, thermal image responses, and/or color imageresponses. In some embodiments, one or more sensors 130 are configuredto capture one or more image responses at one or more wavelengths. Insome embodiments, one or more image responses described herein and/orknown in the art may be specifically excluded from an embodiment, e.g.image responses not including fluorescent image responses.

In some embodiments, one or more image responses include, but are notlimited to, actual images of, for example, cells within the vessellumen. In some embodiments, one or more image responses include imageinformation such as cell shape, cell outline, and/or cell periphery,among others. In some embodiments, one or more image responses includeimage information such as intracellular shapes, intracellular outlines,and/or intracellular peripheries, among others. In some embodiments, oneor more sensors 130 are configured to capture light scattering. In someembodiments, one or more sensors 130 are configured to capture fluidand/or cell velocity.

One or more electromagnetic energy sensors 132 may be configured tomeasure the absorption, emission, fluorescence, or phosphorescence ofone or more targets. Such electromagnetic properties may be inherentproperties of all or a portion of one or more targets (e.g.auto-fluorescence), or may be associated with materials added orintroduced to the body, surface, lumen, interior, and/or fluid, such astags or markers for one or more targets. One or more targets mayinclude, but are not limited to, one or more cells.

In some embodiments, one or more sensors 130 are configured to detect afluorescent response at a single wavelength of electromagnetic energy,at two wavelengths of electromagnetic energy, at multiple wavelengths ofelectromagnetic energy, or over extended-spectrum electromagneticenergy. In some embodiments, one or more sensors 130 are configured todetect excitation energy and/or ablation energy.

In some embodiments, one or more sensors 130 are configured to detect acumulative (optionally fluorescent) response over a time interval. Insome embodiments, one or more sensors 130 are configured to detect a(optionally fluorescent) response at a specific time interval and/or ata specific time. In some embodiments, one or more sensors 130 areconfigured to detect a time-dependent (optionally fluorescent) response.In illustrative embodiments, the cumulative response is determined overmilliseconds, seconds, and/or minutes following excitation. In someembodiments, the response is detected over millisecond, second, and/orminute time intervals following excitation. In some embodiments, theresponse is detected approximately femtoseconds, picoseconds,nanoseconds, milliseconds, seconds, and/or minutes after excitation.

In some embodiments, one or more sensors 130 are configured to becalibrated optionally at least partially based an expected baselineimage response (e.g. normal image response) for the fluid, tissue,cells, and/or lumen. As used herein, the term “normal image response”may include the detected intrinsic image response of one or more fluid,tissue, cells, and/or lumen as determined by researchers and/or medicalor veterinary professionals for subjects of a certain age, ethnicity,etc. who do not have pathological conditions (e.g. control subjects).“Normal image response” may include the intrinsic detected imageresponse of fluid, tissue, cells, and/or lumen of a subject prior to apathological condition and/or of a comparable location not affected bythe pathological condition.

In some embodiments, one or more sensors 130 may be configured to detecta condition of interest including, but not limited to, a temperature, apressure, a fluid flow, an optical absorption, optical emission,fluorescence, or phosphorescence, an index of refraction at least onewavelength, an electrical resistivity, a density or sound speed, a pH,an osmolality, the presence of an embolism, the presence (or absence) ofan object (such as a blood clot, a thrombus, an embolus, a plaque, alipid, a gas bubble, an aggregate, a cell, a specific type of cell, acellular component or fragment, a collection of cell, a gamete, apathogen, or a parasite), and/or the presence (or absence) of asubstance such as a biological marker, an antibody, an antigen, apeptide, a polypeptide, a protein, a complex, a nucleic acid, a celland/or a cell of a particular type, a cellular component, an organelle,a pathogen, a lipid, a lipoprotein, an alcohol, an acid, an ion, animmunomodulator, a sterol, a carbohydrate, a polysaccharide, aglycoprotein, a metal, an electrolyte, a metabolite, an organiccompound, an organophosphate, a drug, a therapeutic, a gas, and/or apollutant, for example.

As used herein, the term “target” may include a material of interest,optionally cells of interest such as, but not limited to blood cellsand/or lymph cells. As used herein the term “possible and/or potentialtargets” includes entities having characteristics suggestive of targets,but not yet confirmed as targets. Materials of interest may include, butare not limited to, materials identifiable by one or more captured imageresponses (individually or as an aggregate signal). Such materials mayinclude, but are not limited to, a blood clot, a thrombus, an embolus,an aggregate, a cell, a specific type of cell, a cellular component, anorganelle, a collection or aggregation of cells or components thereof, apathogen, an infected cell (e.g. virally-infected and/orparasite-infected), or a parasite.

One or more targets may include, but are not limited to, cancer cells,microbial cells, and/or infected cells. One or more cancer cells mayinclude, but are not limited to, neoplastic cells, metastatic cancercells, precancerous cells, adenomas, and/or cancer stem cells. Cancertypes may include, but are not limited to, bladder cancer, breastcancer, colon cancer, rectal cancer, endometrial cancer, kidney (renal)cancer, lung cancer, leukemia, melanoma, non-Hodgkin's Lymphoma,pancreatic cancer, prostate cancer, skin (non-melanoma) cancer, andthyroid cancer. Cancers may include, but are not limited to, bone,brain, breast, digestive, gastrointestinal, endocrine, eye,genitourinary, germ line, gynecological, head and neck,hematologic/blood, leukemia, lymphoma, lung, musculoskeletal,neurologic, respiratory/thoracic, skin, and pregnancy-related.

Microbial cells (microorganisms) may include, but are not limited to,bacteria, protists, protozoa, fungi, and/or amoeba. Pathogens mayinclude, but are not limited to, bacteria, viruses, parasites, protozoa,fungi, and/or proteins. Bacteria may include, but are not limited to,Escherichia coli, Salmonella, Mycobacterium spp., Bacillus anthracis,Streptococcus spp., Staphylococcus spp., Francisella tularensis, and/orHelicobacter pylori. Viruses may include, but are not limited to,Hepatitis A, B, C, D, and/or E, Influenza virus, Herpes simplex virus,Molluscum contagiosum, and/or Human Immunodeficiency virus. Protozoa mayinclude, but are not limited to, Cryptosporidium, Toxoplasma spp.,Giardia lamblia, Trypanosoma spp., Plasmodia spp. and/or Leishmania spp.Fungi may include, but are not limited to, Pneumocystis spp., Tinea,Candida spp., Histoplasma spp., and/or Cryptococcus spp. Parasites mayinclude, but are not limited to tapeworms, helminthes, and/orroundworms. Proteins may include, but are not limited to, prions.

Embodiments of one or more device 100, 200, and/or 300 may includecontrol circuitry 150 coupled to one or more sensors, and responsive toat least partially identify one or more targets during an expectedtransit time (optionally residence time) of the one or more targetsthrough a detection area in one or more blood vessel or lymph vessel atleast partially based on one or more captured image response. In someembodiments, the control circuitry 150 is responsive to identify one ormore predicted future locations of the one or more targets at leastpartially based on the one or more image responses. In some embodiments,the control circuitry 150 is responsive to identify the effect of theablation energy on the one or more targets at least partially based onthe one or more image responses.

Embodiments of one or more device 200, include control circuitry 150coupled to the one or more sensors 130, and responsive to at leastpartially identify one or more targets during an expected transit time(optionally residence time) of the one or more targets through adetection area in, or proximal to, the local bypass 210. Embodiments ofone or more device 300, include control circuitry 150 coupled to the oneor more sensors 130, and responsive to at least partially identify oneor more targets during an expected transit time (optionally residencetime) of the one or more targets through a detection area in, orproximal to, one or more reservoirs 310.

As used herein the term “expected transit time” includes, but is notlimited to, the amount of time calculated and/or predicted to elapsewhile one or more possible targets are within the approximate boundariesof the detection area. Methods and calculations for predicting this timeare described herein and/or known in the art. As used herein, the term“detection area” includes, but is not limited to, an area from which oneor more sensors receive image responses and/or image information.

In some embodiments, the control circuitry 150 is configured to controlone or more of one or more energy sources 110, one or more sensors 130,and/or one or more power sources 160. In some embodiments, the controlcircuitry is configured to control one or more of one or more insert170, one or more vessel attachment units 180, and/or one or more vessellumen anchors 190. In some embodiments, the control circuitry 150 may bedirectly coupled, indirectly coupled, and/or wirelessly coupled to oneor more energy sources 110, one or more sensors 130, and/or one or morepower sources 160. In some embodiments, the control circuitry 150 may bedirectly coupled, indirectly coupled, and/or wirelessly coupled to oneor more of one or more insert 170, one or more vessel attachment units180, and/or one or more vessel lumen anchors 190.

Control circuitry 150 may be electrical circuitry and/or other types oflogic/circuitry including, for example, fluid circuitry,chemo-mechanical circuitry, and other types of logic/circuitry thatprovide equivalent functionality. The control circuitry 150 may includeat least one of hardware, software, and firmware; in some embodimentsthe control circuitry may include a microprocessor. The controlcircuitry 150 may be located in or on the structural element of a deviceand/or at a location separate from the structural element. Controlcircuitry may be internal and/or external to the subject.

There is little distinction left between hardware and softwareimplementations of aspects of systems; the use of hardware or softwareis generally (but not always, in that in certain contexts the choicebetween hardware and software can become significant) a design choicerepresenting cost vs. efficiency tradeoffs. There are various vehiclesby which processes and/or systems and/or other technologies describedherein can be effected (e.g., hardware, software, and/or firmware), andthat the preferred vehicle will vary with the context in which theprocesses and/or systems and/or other technologies are deployed. Forexample, if an implementer determines that speed and accuracy areparamount, the implementer may opt for a mainly hardware and/or firmwarevehicle; if flexibility is paramount, the implementer may opt for amainly software implementation; or, yet again alternatively, theimplementer may opt for some combination of hardware, software, and/orfirmware.

In some embodiments, the control circuitry 150 is responsive to at leastpartially and/or completely identify one or more targets at leastpartially based on one or more of pattern recognition and/or shaperecognition. In illustrative embodiments, amoeba, fungi, and/or protistsmay be identified through pattern and/or shape recognition. In someembodiments, the control circuitry 150 is responsive to at leastpartially and/or completely identify one or more targets at leastpartially based on an actual image optionally of one or more possibletargets, optionally one or more cells. In illustrative embodiments, oneor more amoeba and/or malaria-infected red blood cells may be identifiedby actual image. In some embodiments, the control circuitry 150 isresponsive to at least partially and/or completely identify one or moretargets at least partially based on relative and/or absolute size,optionally of one or more possible targets, optionally of one or morecells. In illustrative embodiments, one or more cancer cells may beidentified at least partially based on size, either absolute, orcompared with other cells. In some embodiments, the control circuitry150 is responsive to at least partially and/or completely identify oneor more targets at least partially based on surface features. Inillustrative embodiments, one or more virally-infected cells and/orpathogen-infected cells may be identified based on changes in membranemorphology and shape, including for example blebs and knobs.

In some embodiments, the control circuitry 150 is responsive to identifyselect one or more characteristics of energy for eliciting an imageresponse (e.g. excitation energy). In some embodiments, the controlcircuitry 150 selects one or more characteristics of energy foreliciting an image response responsive to one or more characteristics ofa prior the image response and/or the energy selected to elicit theprior image response. In some embodiments, the control circuitry 150selects one or more characteristics of energy for eliciting an imageresponse responsive to input from external control circuitry. In someembodiments, the control circuitry 150 selects one or morecharacteristics of energy for eliciting an image response responsive toone or more characteristics of a known target, for examplecharacteristics designed specifically identify the presence or absenceof a particular cell and/or pathogen. In some embodiments, the controlcircuitry 150 selects one or more characteristics of energy foreliciting an image response in a pre-programmed manner.

In some embodiments, the control circuitry 150 is responsive to at leastpartially and/or completely identify one or more targets and/or targetarea at least partially based on one or more of one or more temporallocations, one or more spatial locations, and/or one or moretemporal-spatial locations of the one or more identified targets. Insome embodiments, the control circuitry 150 is responsive to at leastpartially and/or completely identify one or more targets and/or targetarea at least partially based on one or more of the velocity, thevibratory dynamic response, the angular response, and/or the inertialresponse of the one or more targets. In some embodiments, the controlcircuitry 150 is responsive to at least partially and/or completelyidentify one or more targets and/or target area at least partially basedon predicting one or more future locations of the one or more targets.

In some embodiments, the control circuitry 150 identifies a target,target area, and/or target cells by determining one or more of thedirection, the distance, the lumen depth, the time, and/or thecoordinates from which an image response originated, optionally inrelation to the energy used to elicit the one or more image response. Insome embodiments, the control circuitry 150 identifies a target, targetarea, and/or target cells by analysis of one or more characteristics ofan image response (e.g. presence and/or absence of an image responseand/or density of a image response—grouping of cells that if non-groupedwould not be considered a target), optionally including but not limitedto, the electromagnetic spectrum, or parts thereof. In some embodiments,the control circuitry 150 identifies a target, target area, and/ortarget cells in real time.

As used herein, the term “target area” includes, but is not limited to,an area identified, determined, and/or predicted for at least partiallyablating (optionally damaging, destroying, making non-viable, amongothers) one or more targets. In some embodiments, a target area is anapproximately fixed location through which one or more targets arepredicted to pass and/or actively moved toward (e.g. funneled, passedthrough a narrowing insert, passed through a valve, etc.). In someembodiments, a target area is determined by the presence (or predictedpresence) of one or more targets.

In some embodiments, the control circuitry 150 is responsive to selectone or more characteristics of ablation energy for at least partiallyablating a target, target area, and/or target cells. In someembodiments, the control circuitry 150 selects one or morecharacteristics of ablation energy for at least partially ablating atarget, target area, and/or target cells responsive to one or morecharacteristics of the image response and/or the energy selected toelicit the image response. In some embodiments, the control circuitry150 increases the ablation energy responsive to an increase in the imageresponse, and/or decreases the ablation energy responsive to a decreasein the image response. In some embodiments, the control circuitry 150selects one or more characteristics of the ablation energy at leastpartially responsive to detection of one or more wavelengths of theimage response.

In some embodiments, the control circuitry 150 is responsive to updatetargeting information on the basis of movement of part or all of adevice 100, 200, and/or 300 and/or a target and/or target area. Inillustrative embodiments, such target updating may be useful when theablating energy may be delivered at a time (optionally substantially)later than the time at which an image response is detected, or when thetarget is moving in relation to the ablation energy source. In thiscase, the detected location may be updated to take into account possiblemotion of the target area and/or the device.

Motion of the image response location can be updated by registering thedetected image response location relative to other, updatable, locationinformation. In one example, the detected image response location isregistered relative to fiducials within the individual. Then, thelocation of the fiducials is updated, and the site of the image responselocation at such time can be predicted based upon its known registrationrelative to the fiducial locations. In another example, the detectedimage response location is registered relative to features within animage of a related portion of the individual. Then, the image is updatedand the location of the image response location at such time can bepredicted based upon its known registration relative to the imagefeatures.

Motion, which may include location and/or orientation, of the device canbe updated by a variety of methods, including inertial navigation,measurements based on beacons or fiducials, measurements based onorientation sensors, or combinations of such techniques. Inertialnavigation can be performed with the support of accelerometers on thedevice, and may also incorporate use of gyroscopic sensors on thedevice. Beacons and/or fiducials can be used to measure the device'smotion; the beacons or fiducials may be on the device and their locationor direction measured by remote sensors. Alternatively, measurements ofremote beacons or fiducials may be made by sensors on the device.Combined systems may be used, with mixtures of remote and on-boardsensors, measuring the location or direction of remote or on-boardbeacons or fiducials. Orientation sensors, such as tilt sensors may beused to provide information of one or more aspects of the device'sorientation. Motion information obtained from different sources ormethods can be combined together to give improved motion estimates,using techniques such as nonlinear filtering, least-squares filtering,Kalman filtering, etc.

The updated image response location may then be combined, via acoordinate translation and rotation, with the updated position andlocation of the device. This results in updated coordinates ordirections of the image response location with respect to the device,and can be used to direct the delivery of ablation energy.

In some embodiments, control circuitry 150 receives information from oneor more sensors 130 and/or one or more external sources. Information mayinclude, but is not limited to, a location of an untethered device,allowable dose limits (e.g. of energy for excitation and/or ablation),release authority (e.g. for release of energy for excitation, ablation,and/or release from an affixed and/or stationary location), controlparameters (e.g. for energy release, for motion, for power, for sensors,etc.), operating instructions, and/or status queries.

In some embodiments, control circuitry 150 is feedback controlled,optionally from information from one or more sensors 130, and/or one ormore external sources. In some embodiments, control circuitry 150 ismonitored by one or more external sources, provides outputs to one ormore sources, and/or sends outputs to one or more sources. In someembodiments control circuitry is remote-controlled, wirelesslycontrolled, programmed, and/or automatic. Equipment, methods, andsoftware associated with control circuitry are described herein and/orknown in the art (see e.g., U.S. Patent Applications 2007/0066939,2007/0225633, Ser Nos. 11/414,164 and 11/414,149).

Embodiments of one or more device 100, 200, and/or 300 optionallyinclude a power source 160 (see e.g., FIG. 6). One or more power sources160 may be configured to provide power to one or more of one or morecontrol circuitry 150, one or more sensor 130, and/or one or more energysource 110. One or more power sources 160 may be configured to providepower to one or more of one or more inserts 170, one or more vesselattachment units 180, and/or one or more vessel lumen anchors 190. Oneor more power sources 160 may be configured to provide power to one ormore of one or more local bypass 210 and/or one or more reservoirs 310.

Power sources 160 may include, but are not limited to, one or morebatteries 161, fuel cells 162, energy scavenging 163, electrical 164,and/or receivers 165 located on and/or in one or more parts of the oneor more devices or separately from the one or more devices. The one ormore batteries may include a microbattery such as those available fromQuallion LLC (http://www.quallion.com), may be designed as a film (U.S.Pat. Nos. 5,338,625 and 5,705,293), or may be a nuclear battery. The oneor more fuel cells may be enzymatic, microbial, or photosynthetic fuelcells or other biofuel cells (US2003/0152823A1; WO03106966A2 MiniatureBiofuel cell; Chen T et al. J. Am. Chem. Soc. 2001, 123, 8630-8631, AMiniature Biofuel Cell), and may be of any size, including the micro- ornano-scale.

The one or more energy-scavenging devices may include apressure-rectifying mechanism that utilizes pulsatile changes in bloodpressure, for example, or an acceleration-rectifying mechanism as usedin self-winding watches, or other types of flow rectifying mechanismscapable of deriving energy from other flow parameters. The one or moreelectrical power sources may be located separately from the structuralelement of the device and connected to the structural element by a wire,or an optical power source located separately from the structuralelement and connected to the structural element by a fiber-optic line orcable. The one or more power receivers may be capable of receiving powerfrom an external source, acoustic energy from an external source, and/ora power receiver capable of receiving electromagnetic energy (e.g.,infrared energy) from an external source.

In illustrative embodiments, one or more power sources 160 areoptionally part of and/or are configured to open and/or close one ormore valves, to attach or detach one or more anchors, to insert orremove one or more local bypass couplings, or to change conformations ofone or more inserts. One or more of the mechanisms may includemechanical or micromechanical structures driven by at least one motor,micromotor, or molecular motor, or by expansion or change inconfiguration of a shape change polymer or metal. A molecular motor maybe a biomolecular motor that runs on a biological chemical such as ATP,kinesin, RNA polymerase, myosin dynein, adenosinetriphosphatesynthetase, rotaxanes, or a viral protein.

In some embodiments, the power source 160 optionally includes a powertransmitter capable of transmitting power from one or more device to asecondary location or vice versa. The power transmitter may be capableof transmitting at least one of acoustic power, electrical power, oroptical power, among others. The secondary location may be, for example,another device within the body, either in a body lumen or elsewhere thatincludes a power receiver and structures for using, storing and/orre-transmitting the received power.

In some embodiments, the power source 160 optionally includes a powerreceiver optionally configured to receive power from one or moreexternal sources. Power may be received wirelessly or through a wiredconnection, for example. Power may be received from a battery pack orother power source (optionally continually renewable, such as motionre-charged) that can be worn or attached to a subject, and/or receivedfrom chargers present in buildings, homes, and/or care-giving settings(e.g. clinic and/or hospital).

In one aspect, the disclosure is drawn to one or more methods forimaging and optionally ablating one or more targets, optionally usingone or more device 100, 200, and/or 300 described herein. Although oneor more methods may be presented separately herein, it is intended andenvisioned that one or more methods and/or embodiments of one or moremethods may be combined and/or substituted to encompass the fulldisclosure. In some embodiments, one or more methods may include one ormore operations, and be implemented using one or more computing devicesand/or systems.

Embodiments of one or more methods for screening for, or against, one ormore targets, optionally using a system including one or more device100, 200, and/or 300, include locally capturing image informationassociated with one or more blood vessel or lymph vessel in a subject;analyzing the image information to at least partially identify one ormore targets in real time; and optionally determining the absolutenumbers and/or ratio (as compared to a control population of cells, forexample) of one or more targets over a time interval.

Embodiments of one or more methods for imaging and optionally ablatingone or more targets, optionally using a system including one or moredevice 100, 200, and/or 300, include locally capturing image informationassociated with one or more blood vessel or lymph vessel in a subject;analyzing the image information to at least partially identify one ormore targets in real time (e.g. during residence time in the detectionand/or destruction areas); selecting a target area at least partiallybased on the one or more identified targets; and locally providingenergy to the target area in real time (e.g. during residence time inthe detection and/or destruction areas), the energy having a magnitudeselected to at least partially ablate the one or more targets.

Embodiments of one or more methods for modulating the biologicalactivity of one or more targets in a subject, optionally using a systemincluding one or more device 100, 200, and/or 300, include locallycapturing image information associated with one or more blood vessel orlymph vessel in the subject; analyzing the image information to at leastpartially identify one or more targets; and locally providing energy inan amount sufficient to at least partially impair the biologicalactivity (e.g. at least partially inactivate) of the one or moreidentified targets.

Embodiments of one or more methods of treating, ameliorating, and/orpreventing a disease or disorder in a subject in need of such treatment,optionally using a system including one or more device 100, 200, and/or300, include locally capturing image information associated with one ormore blood vessel or lymph vessel in a subject; analyzing the imageinformation to at least partially identify one or more targets in realtime (e.g. during residence time in the detection and/or destructionareas); selecting a target area at least partially based on the one ormore identified targets; and locally providing energy to the target areain real time (e.g. during residence time in the detection and/ordestruction areas), the ablation energy having characteristicsappropriate to at least partially ablate the one or more identifiedtargets, wherein the one or more identified targets are associated withthe disease or disorder.

Embodiments of one or more methods include affixing one or more devices100, 200, and/or 300 to a location in, or proximal to, a blood vessel orlymph vessel. As used herein, the term “affixing” may include, but isnot limited to one or more processes by which the one or more devicesmay be held stationary in the lumen or internal location. The affixationmay be temporary and/or permanent as described herein. Mechanisms bywhich one or more device may become affixed are known in the art and/ordescribed herein.

Embodiments of one or more methods include locally and/or externally(e.g. external to the subject) providing energy, optionallyelectromagnetic energy and/or acoustic energy (e.g. ultrasonic energy)selected to induce an image response (e.g. elicit image information), toa target, target area, target cell, target tissue, internal location,and/or blood or lymph vessel, optionally the vessel lumen.Electromagnetic energy optionally includes, but is not limited to,optical energy (e.g. visible light), infrared energy, ultravioletenergy, and/or radiofrequency energy. Providing electromagnetic energyoptionally includes using a laser or other device to provide opticalenergy to a target.

Parameters associated with the selection of energy to induce an imageresponse (and/or elicit image information) include, but are not limitedto, the target, the environment associated with the target, thecharacteristics of the energy source 110, optionally an electromagneticenergy source 111, and/or an acoustic energy source 120, and/or thecharacteristics of the one or more sensors 130.

The parameters associated with the target include, but are not limitedto, the distance of the target from the energy source 110, the depth ofthe target beneath a surface (e.g. a lumen wall), the inherentcharacteristics of the target (e.g. fluorescence), the size of thetarget, and/or the movement of the target (e.g. stationary, steadymovement, variable movement, predictable movement, etc.).

The parameters associated with the environment include, but are notlimited to, location, milieu (e.g. many cells, few cells), movement(e.g. stationary, steady movement, intermittent movement, predictablemovement, etc.), physiologic parameters (e.g. pH, temperature, etc.),and/or non-target image responses (e.g. background fluorescence,non-specific fluorescence, intrinsic non-target fluorescence, etc.).

The parameters associated with the characteristics of theelectromagnetic energy source 111 include, but are not limited to, thewavelengths available for selection (e.g. single, two-photon, multiple,extended-spectrum, etc.), the strength of the emitted electromagneticenergy (e.g. limitations on distance and/or depth, etc.), the type ofoutput (e.g. pulsed, two-photon, etc.), directionality (e.g. limited,variable, varied, etc.), and/or spatial parameters (e.g. limited,focused, collimated, etc.).

The parameters associated with the characteristics of the sensor 130include, but are not limited to, the detection limits associated withwavelength (e.g. single, two-photon, multiple, extended-spectrum, etc.),signal strength (e.g. sensitivity of detection, level above background,etc.), and/or time (e.g. detects cumulative readings over time, detectsreadings at certain time intervals, or at a certain time postexcitation, etc.). Parameters associated with the characteristics of thesensor 130 include, but are not limited to, the type of image responseand/or image information captured by the sensor 130.

In some embodiments, image information includes, but is not limited to,one or more of acoustic image information (e.g. ultrasonic imageinformation), thermal image information, and/or electromagnetic imageinformation, optionally radiofrequency image information and/or opticalimage information (e.g. visible light image information, infrared imageinformation, ultraviolet image information, and/or color imageinformation). In some embodiments, image information includes scatteringresponse information (e.g. light scatter, but optionally other energyscatter responses) and/or absorptive response information (e.g. lack ofback scatter from energy excitation). In some embodiments, imageinformation includes, but is not limited to, one or more of spatialand/or temporal information, and/or velocity information relating tofluid and/or cellular flow (e.g. one or more possible targets in thelumen). Appropriate sensors 130 for capturing image information andtheir selection are known to one of skill in the art and/or describedherein.

Embodiments of one or more methods include selecting the energy toinduce the image response. Methods for selecting include, but are notlimited, manually, remotely, automatically, programmably, wirelessly,and/or using control circuitry. Manually selecting includes, but is notlimited to, manually operating one or mechanism (e.g. a switch, dial,button, setting, etc.) on one or more device 100, 200, and/or 300 thatcontrols the characteristics of the energy emitted from one or moreenergy source 110. Remotely selecting includes, but is not limited to,optionally wirelessly interacting with circuitry on one or more device100, 200, and/or 300 that controls the characteristics of the energyemitted from one or more energy source 110. Programmably selectingincludes, but is not limited to, optionally using control circuitry 150,optionally part of one or more device 100, 200, and/or 300 (e.g.internal and/or external to the subject), programmed, optionallymanually, remotely, and/or wirelessly, to select the characteristics ofthe energy emitted from one or more energy source 110. Methods forprogramming control circuitry and applicable control circuitry arewell-known to one of skill in the art and/or described herein.

Embodiments of one or more methods include monitoring the energyselected to induce an image response and/or elicit image information,monitoring the energy selected to ablate the target, optionallyelectromagnetic energy, acoustic energy, and/or particle beam energy.Methods of monitoring electromagnetic energy, acoustic energy and/orparticle beam energy are known in the art and/or described herein.Methods include, but are not limited to, using sensors able to detectone or more characteristics of the energy.

Embodiments of one or more methods include capturing, optionally locally(e.g. using one or more sensors 130), image information associated withone or more blood vessel and/or lymph vessel, optionally the vessellumen. In some embodiments, image information is captured sequentially.In illustrative embodiments, image information is captured by a firstsensing system (e.g. sensor 130, energy source 110, and/or controlcircuitry 150), of fluid and/or cellular flow in a blood or lymph vessellumen. If analysis optionally by control circuitry 150 of the imageinformation indicates the presence of one or more possible targets, thenadditionally image information is captured, optionally by a secondsensing system (e.g. sensor 130, energy source 110, control circuitry150 and/or insert 170) further downflow from the first sensing system.This second sensing system may optionally include an insert to directthe one or more possible targets to a detection area for sensing usingone or more optionally different types of sensors 130.

Embodiments of one or more methods include detecting an image response.Methods of detecting an image response include, but are not limited to,detecting an image response using one or more sensors 130, detectors,and/or monitors. Sensors 130, detectors, and/or monitors appropriate fordetection and/or monitoring of the image response are known in the artand/or described herein. As used herein, the term “detecting” mayinclude any process by which one or more characteristics of an imageresponse may be measured and/or quantified.

Embodiments of one or more methods include identifying a target forablation (e.g. target area, target cells, and/or target tissues). Asused herein, the term “identifying a target” may include, but is notlimited to, processes including selecting a target and/or determining atarget. One or more methods for identifying a target for ablationoptionally include analyzing an image response, image information,and/or other information, optionally using control circuitry 150,optionally in real time.

Embodiments of one or more methods include analyzing image information,optionally using control circuitry 150. In some embodiments, analyzingthe image information includes comparing the image information to one ormore of reference image information and/or target image information (seee.g. U.S. Patent Applications 2007/0066939 and 2007/0225633). In someembodiments, this comparison includes comparing one or more of cellshape and/or cell outline information with reference and/or targets cellshapes and/or cell outline information. In some embodiments, thiscomparison includes comparing one or more of intracellular shape and/orintracellular outline information with reference and/or targetintracellular shape and/or intracellular outline information. In someembodiments, analyzing the image information includes performing one ormore of pattern recognition or shape recognition analysis. Software,systems, and/or firmware, for example, for performing these calculationsand analyses is known in the art and/or described herein.

In some embodiments, analyzing the image information includesdetermining temporal and/or spatial information associated (and/orcorrelated) with the image information. In some embodiments, analyzingthe image information includes determining velocity of the fluid and/orcellular flow (e.g. velocity of target movement) associated (and/orcorrelated) with the image information. In some embodiments, analyzingthe image information includes predicting future spatial and/or temporallocations associated with the image information. Software, systems,and/or firmware, for example, for performing these calculations andanalyses is known in the art and/or described herein.

In illustrative embodiments, image information is analyzed either bycontrol circuitry in the subject and/or by control circuitry external tothe subject, optionally transmitted wirelessly. The control circuitryanalyzes the image information in real time and/or within the expectedtransit time through the detection area and/or to the destruction area(e.g. target area). If one or more targets is identified for ablationthe target may be ablated in real time, and/or its arrival in adestruction area may be predicted using control circuitry. In thisevent, control circuitry optionally uses information relating tomeasurements of fluid and/or cellular for determined from the imageinformation to predict the time for ablation and/or the location forablation. Software, systems, and/or firmware, for example, forperforming these calculations and analyses is known in the art and/ordescribed herein

Analyzing an image response to at least partially identify a target forablation may include, but is not limited to, evaluating an imageresponse at least partially in reference to baseline, background, and/ornon-specific image responses, as well as expected, reference, and/ornormal image responses (e.g. baseline fluorescence, backgroundfluorescence, expected fluorescence, normal fluorescence, referencefluorescence, non-specific fluorescence, and/or intrinsic non-targetfluorescence, etc.). Analyzing an image response may include, but is notlimited to, subtractively determining an image response, optionally atarget fluorescent response (e.g. subtracting the non-targetfluorescence from the total fluorescence to determine the targetfluorescence). Analyzing an image response may include, but is notlimited to, evaluating an image response at least partially based ondetection at one or more wavelengths (e.g. single, multiple,extended-spectrum, etc.), based on time (e.g. one or more times, timeintervals, and/or over time, etc.), based on direction (e.g. oforigination of the emission, etc.), based on strength, and/or based ondistance (e.g. of origination of emission from a sensor). Inillustrative embodiments, analyzing an image response may include, butis not limited to, identifying “clumps” and/or “groups” of cells that inanother context might be considered “normal”, but that are not normallygrouped and so may be a target for ablation (see e.g. U.S. PatentApplications 2007/0066939 and 2007/0225633).

In illustrative embodiments, an analyzed target image response is usedto determine the direction from which the response originated in orderto provide ablation energy to the location and/or general area. Inillustrative embodiments, an analyzed target image response is used todetermine the coordinates from which the response originated in order toprovide ablation energy to the location and/or general area.

As used herein, the term “location” may include, but is not limited to,one or more of a direction, an area, a depth, a site, or a size, etc. Alocation may be defined by spatial coordinates and/or temporalcoordinates. A location may be defined as precisely as the cellularlevel, for example, or as broadly as a general area, or a generaldirection. Methods of determining a location based on the detection of aimage response are known in the art and/or described herein. Inillustrative embodiments, a target location may be the lumen of a bloodvessel following detection of a target image response.

Analyzing other information to at least partially identify a target forablation may include, but is not limited to, analyzing informationoptionally provided by one or more sensors 130 (e.g. intrinsic and/orextrinsic to one or more device 100, 200 and/or 300) and/or provided byone or more external sources (e.g. remotely and/or wirelessly, etc.).Analyzing information optionally provided by one or more sensors mayinclude analyzing information including, but not limited to,environmental information such as, but not limited to, pH, temperature,pressure, chemistry, physiological measurements, dietary measurements,biological measurements, etc. In illustrative embodiments, identifying atarget fluorescent response is a least partially based on identifyingthe pH of the environment, optionally detecting an acidic pH. Analyzinginformation optionally provided by one or more external sources mayinclude analyzing information including, but not limited to,environmental information and/or medical and/or veterinary professionalinformation.

Analyzing an image response to at least partially identify a target forablation may include, but is not limited to, evaluating an imageresponse in real time. As used herein, the term “in real time” mayinclude, but is not limited to, immediate, rapid, not requiring operatorintervention, automatic, and/or programmed. In real time may include,but is not limited to, measurements in femtoseconds, picoseconds,nanoseconds, milliseconds, as well as longer, and optionally shorter,time intervals. In illustrative embodiments, analysis in real time issufficiently rapid such that the target and the device have not movedand/or changed positions/locations significantly with respect to eachother such that ablation energy sent along the path of the initialexcitation energy will cause damage to the one or more identifiedtargets. In illustrative embodiments, an image response is detected andanalyzed, and a target is identified without operator intervention andthe target ablation information is provided to an energy source.

In some embodiments, in real time may include during a period ofresidence of the one or more targets in a detection area and/or anablation area. One or more of the diction area and/or the ablation areamay be in the local bypass 210 and/or in a reservoir 310. In someembodiments, on or more of analyzing image information and/or providingablation energy may be performed during a period of residence of the oneor more targets.

Embodiments of one or more methods include providing energy to at leastpartially ablate a target, optionally from one or more local energysources 110 and/or from one or more external energy sources (e.g.external to the subject). One or more methods include providing energyto at least partially ablate a target in real time. As used herein theterm “ablation or ablate” may include, but is not limited to, processesincluding destroying, modifying, removing, inactivating, and/oreliminating, in part or in whole, a target and/or a material ofinterest. As used herein, ablation may include the process of removingmaterial and/or damaging and/or inactivating a biological entity byirradiating it, optionally with a laser beam, optionally with a pulsedlaser, or a continuous wave laser. As used herein, the term“inactivating” includes but is not limited to, damage such that thebiological entity is no longer viable, cannot reproduce, and/or is nolonger infectious.

Energy for ablation may include, but is not limited to, electromagneticenergy, acoustic energy (e.g. ultrasonic energy), X-ray energy, andparticle beam energy. Electromagnetic energy such as light may cause,for example, a photoreaction, molecular bond breakage, heating, or otherappropriate effect. Electromagnetic energy sources 110 may include, butare not limited to, light sources such as light emitting diodes andlaser diodes, or sources of other frequencies of electromagnetic energy,radio waves, microwaves, ultraviolet rays, infra-red rays, optical rays,thermal energy, terahertz beams, and the like.

As used herein, the term “at least partially ablate” may includepartially and/or completely ablating a target. As used herein, the term“completely ablate” may include ablation of a target up to theapplicable limits of detection (e.g. no longer detectable by the sensorsused to detect the image response, no longer detectable over background,and/or no longer statistically significant). As used herein the term“partially ablate” may include ablation less than complete ablation, butwhere at least some detectable ablation occurs. At least some detectionablation includes, but is not limited to, ablation detectable by thesensors used to detect the image response, statistically significantablation, detection by external sensors, and/or detection by inferencefrom other measurements and/or sensor readouts.

Embodiments of one or more methods include locally inhibiting fluidand/or cellular flow associated with one or more blood vessel or lymphvessel, optionally associated with a vessel lumen. In some embodiments,locally inhibiting fluid flow includes locally restricting cellular flowin the lumen. In some embodiments, locally inhibiting fluid flowincludes modifying cellular flow such that one or more cells traversethe lumen in single file and/or traverse a localized region of thelumen. In some embodiments, locally modifying fluid flow includes atleast partially reducing and/or constricting an internal and/or externalcircumference of the vessel lumen. In some embodiments, locallymodifying fluid flow includes locally compressing and/or at leastpartially occluding the lumen. In some embodiments, locally modifyingfluid flow includes activating a local compression mechanism and/orlocal occlusion mechanism associated with the lumen.

As used herein the term “modifying” includes, but is not limited to,changes made to the referent which may be partial and/or complete. Forexample, modifying fluid flow may include increasing and/or decreasingfluid flow and/or inhibiting and/or enhancing fluid flow. Modifyingfluid flow may refer to increasing and/or decreasing the speed of thefluid flow and/or the amount of the fluid flow. Modifying fluid flow mayrefer to changing the direction and/or path of the fluid flow. Thesechanges may be partial (e.g. less than complete inhibition, but yetmeasurable) and/or complete (e.g. no detectable fluid flow can occur,and/or a non-significant amount of fluid flow occurs). Unless indicatedotherwise, generally modification refers to partial, not completemodification (e.g. partial, not complete inhibition). Methods fordetecting changes in fluid and cellular flow are known in the art and/ordescribed herein. To be considered modified, changes are measurable, andoptionally statistically significant differences as compared to theprevious, calculated, and/or reference amounts of fluid flow.

In illustrative embodiments, locally modifying fluid and/or cellularflow may occur using one or more insert 170 and/or one or more valve. Inillustrative embodiments, image information is optionally captured ofthe modified fluid flow, and optionally analyzed by control circuitry150. In some embodiments, ablation and/or modification (inactivationenergy) is provided to the modified fluid flow. For example, imageinformation may be enhanced when captured from fluid and/or cells movingat a reduced speed, or reduction in speed may permit more time foranalysis by control circuitry 150 of the image information, or permitadditional or different types of sensors to capture image information.In illustrative embodiments, inhibition and/or reduction in speed offluid flow (or capture of one or more targets) my facilitate ablation ofone or more targets, either through prediction and/or calculation of apredicted future location or time of passage through a known location,or through directing the one or more targets to a destruction area.

Embodiments of one or more methods optionally include at least partially(optionally completely) diverting fluid flow from and at least partiallyreturning fluid to a lumen of one or more blood vessel and/or lymphvessel, optionally through a local bypass. In some embodiments, thisprocess of diversion and return of fluid flow is controllable and/orprogrammable. In illustrative embodiments, fluid is diverted from avessel lumen optionally through a valve leading to a local bypass (e.g.an optionally optically pure channel) in which additional imageinformation can be captured and optionally ablation can occur. The localbypass may be in line with the vessel lumen, internal to the vessellumen, and or an off-branch from the vessel lumen. Illustrative examplesare provided herein.

In some embodiments, the methods include controllably attaching thelocal bypass to the one or more vessel. In illustrative embodiments, theinsert may be provided to (and removed from) the appropriate locationvia some form of microsurgery. The connections attaching the localbypass in local may optionally be remotely and/or wirelessly and/orprogrammably activated and de-activated to facilitate this process.

In some embodiments, image information is captured associated with thelocal bypass. In some embodiments, the image information is captured inthe vessel lumen upflow and/or downflow of the local bypass, and/or inthe local bypass lumen. In illustrative embodiments, image informationis captured upflow of the local bypass, analyzed by control circuitryand then the valve leading to the local bypass is opened or closeddepending, for example, on whether any possible targets are detected.Once in the local bypass, additional sensing may be performed (or thismay be where all sensing takes place and the bypass opens and closesaccording to a program or parameters other than the presence or absenceof possible targets in the vessel lumen). The local bypass is optionallydesigned for optical imaging such that better measurements areoptionally available. More than one sensor system is optionally presentin the local bypass, and more than one type of imaging may be done onall cells, done randomly on a subset of cells, and/or done sequentiallyon cells depending on earlier sensing results. In illustrativeembodiments, image information is captured downflow of the local bypass(or downflow of the upflow bypass valve) in the vessel lumen, optionallyto document cells that do not enter the bypass lumen, and/or to documentcells exiting the bypass lumen.

In some embodiments, the target area is selected in the local bypass. Insome embodiments, selection of the target area is based at leastpartially on a predicted future path of the one or more targets, and/oron a predicted time of arrival of the one or more identified targets atan identified location in the local bypass.

Some embodiments include locally modulating fluid flow in the localbypass (optionally using a bypass insert 216), optionally reducing fluidflow and/or increasing fluid flow in the local bypass. In someembodiments modulating fluid flow in the local bypass includesmodulating the lumen of the local bypass. Methods relating to modulatingfluid flow in a vessel are discussed herein, and are applicable to thelocal bypass unless context dictates otherwise.

Embodiments of one or more methods include locally collecting one ormore identified targets in one or more reservoirs 310. In someembodiments, image information is captured from the lumen of the one ormore reservoirs. In some embodiments, energy is provided to the lumen ofthe one or more reservoirs to elicit the image information and/or toablate one or more targets. In illustrative embodiments, one or morereservoirs are configured to receive one or more targets (or possibletargets) identified by one or more sensing systems upflow from thereservoir. Within the reservoir, the one or more targets (or possibletargets) optionally undergo additional tests and analysis from one ormore sensing systems optionally including counting the numbers of one ormore targets optionally during a defined time period) and/or are simplycollected for further analysis ex vivo. Information relating to thetargets may be provided to one or more external control circuitry,and/or accessible to one or more external sources through wirelesstechnology.

In some embodiments, the reservoir lumens are accessed from the exteriorof the subject, optionally so that the one or more possible targetsand/or one or more targets can undergo additional tests and analysis exvivo. In illustrative embodiments, the reservoirs are placed tofacilitate external access from the subject and/or medicalprofessionals. Optionally a permanent or semi-permanent conduit may bein place to allow easy access. Optionally access is through a large boreneedle (e.g. biopsy needle).

Embodiments of one or more methods may include combinations includingone or more bypass, one or more insert, one or more reservoir, etc in avariety of combinations and configurations, as well as one or moresensors 130, energy sources 110, control circuitry 150, and powersources 160.

EXAMPLES

The following Examples are provided to illustrate, not to limit, aspectsof the present invention. Materials and reagents described in theExamples are commercially available unless otherwise specified.

Example 1 Detection of Biological Targets in Vessels Using LightScattering

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect specific biologicaltargets based on differential scattering of light. As such, a cell orcells in the vessel circulation may pass through an examination zoneeither incorporated within the device or in close proximity to thedevice. A cell or cells may be, for example, a bacterium, a protozoan, aplatelet, a red blood cell, a lymphocyte, a monocyte, a neutrophil, aneosinophil, a circulating tumor cell or a combination thereof.

For imaging through use of differential scattering, the cell or cellsare illuminated in an examination zone with a focused beam of energy.The beam may be a form of electromagnetic energy such as, for example,white light, laser light, X-rays, or infrared radiation. The devicemeasures the optical interactions of the electromagnetic energy with thecell or cells, such as multiple wavelength absorption, scatter as afunction of angle, or fluorescence as a function of either wavelength orpolarization. The information regarding the optical interactions may becaptured by a photosensor such as, for example, a CCD (charge coupleddevice) and/or a CMOS (complementary metal oxide semiconductor) sensor.

The captured information is processed internally by the device or sentwirelessly to an external processor. In real time, the capturedinformation is compared with preset algorithms defining, for example,the light scattering properties of cells normally found in thecirculation. For example, forward light scattering may provide a roughindication of cell size while side light scattering may provide a roughindication of cellular granularity, membrane complexity, and number oforganelles. Alternatively (or additionally), the captured information iscompared with preset algorithms defining, for example, the lightscattering properties of abnormal blood cells or cells foreign to thecirculation such as bacteria or circulating neoplastic cells, forexample.

Upon identification of an abnormal cell or cells, the information may beprovided to an external source through control circuitry, additionalsensing parameters may be instigated, the cells may be provided to areservoir for storage and optional retrieval, and/or the device may emitradiation sufficient to at least partially modify (or render non-viableor at least of reduced viability) the targeted cell. Alternatively, thedevice triggers emission of radiation from a second component of thedevice positioned downstream from the first detecting device.

Lymphocytes, monocytes, and granulocytes may be differentiated from oneanother under conditions of flow using, for example, a four-parameterlight scattering technique used, for example, in flow cytometry(Terstappen et al. (1988) Cytometry 9:39-43). Electromagnetic energyemitted from a laser at wavelengths from 400 nm to 700 nm, for example,is differentially scattered by a cell or cells in the examination zone.The light scattering intensity may be simultaneously measured, forexample at angles between 1.0 and 2.6 degrees and 3.0 and 11.0 degrees.Eosinophilic granulocytes may be differentiated from neutrophilicgranulocytes by simultaneous measurement of the orthogonal anddepolarized orthogonal light scattering. Platelets and red blood cellsexhibit minimal light scattering at the angles described above and areconsequently excluded from the analysis. Alternatively, red and whiteblood cells may be distinguished by simultaneously observing forward andorthogonal light scatter at a wavelength of 413.1 nm, for example (Ostet al. (1998) Cytometry 32:191-197). Alternatively, a diode laseremitting, for example, at either 670 nm or 780 nm may be used todistinguish lymphocytes, monocytes, neutrophils, and eosinophils using acombination of forward, orthogonal, and depolarized orthogonal scatter(Doornbos et al. (1993) Cytometry 14:589-594).

Lymphocytes, granulocytes, and red blood cells may also bedifferentiated from one another based on forward and side lightscattering under conditions of flow in an in vivo analysis, for example,of a surgically exposed mesentery artery (see, e.g., U.S. Pat. No.7,264,794 B2).

An abnormal white blood cell associated with, for example, acutemyeloblastic leukemia (AML), may be differentiated by light scatter. AMLis characterized by uncontrolled proliferation of malignant myeloidprogenitors in the bone marrow, at the expense of normal proliferationof white blood cells, red blood cells, and platelets. These immaturewhite blood cells or blasts are arrested in their maturation process andcan easily egress from the bone marrow into the circulation. Sarcomasfound in various solid tissues may arise from metastasis of AML(Konoplev & Bueso-Ramos (2006) Ann. Diag. Path. 10:39-65).

AML blast cells may be differentiated from T-lymphocytes, for example,by measuring low angle forward light scatter and orthogonal lightscatter (Vidriales et al. (1995) J. Clin. Pathol. 48:456-462). As such,the device may be used to induce and detect the patterns of forward andorthogonal light scatter of AML blast cells, for example, in thecirculation. These patterns may be compared with those of normal whiteblood cells using preset algorithms.

Differential light scattering may also be used to detect circulatingtumor cells derived from metastasis of solid tumors. In general, acirculating tumor cell is characterized by its large size, immatureappearance, increased nuclear to cytoplasmic ratio, abnormally shapednuclei, and disproportionately large nucleolus or multiple nucleoli(Moore et al. (1960) Cancer 13:111-117).

The size differential between a circulating tumor cell and components ofthe blood may be used to specifically detect the cancerous cells. Forexample, the average diameter of neutrophils, red bloods cells, andplatelets is 10.5-12.5 microns, 7-8 microns, and 3 microns,respectively. In contrast, the average size of circulating tumor cellsisolated from patients with breast, colon, stomach and lung cancersrange from 18.3 to 20.6 microns in diameter (Moore et al. (1960) Cancer13:111-117). Similarly, circulating neuroblastoma tumor cells aregreater than 20 microns in diameter (Mohamed et al. (2004) IEEETransactions on Nanobioscience, 3:251-256).

While neuroblastoma is a radiosensitive tumor, long-term control isdifficult due to metastasis. Therefore, the ability to detect and ablatecirculating tumor cells, such as neuroblastoma cells, may aide in thetreatment of this cancer. As such, the size of a cell or cells passingthrough the examination zone is determined using forward lightscattering. The size, as measured for example in diameter, is comparedwith known parameters regarding the size of normal blood components.Detection of an abnormally large cell may signal the presence of acirculating tumor cell and may trigger an ablation response.

An untethered device configured to function in or proximal to a bloodvessel or lymph vessel may also be used to detect circulating bacteriarelative to other cellular components of the circulation based on sizeanalysis using light scattering. Bacteria are on average 0.2 to 1.0microns in diameter as compared to 1.5 to 3.0 microns for platelets, forexample. Staphylococcus aureus bacteria, for example, are perfectlyround and approximately 1 micron in diameter. As such, a bacterium maybe distinguished from platelets and other larger blood cell componentsbased on size as described herein. The diameter as well as the length ofthe rod-shaped Escherichia coli bacteria, for example, may be determinedusing polarized light scattering, as described by Bronk et al. ((1995)Biophysical J. 69:1170-1177).

Other pathogens may be detected in the circulation based on sizeanalysis and light scattering. For example Trypanosoma brucei gambiense,a blood borne protozoan associated with African sleeping sickness, has aunique elongated cellular shape relative to the predominantly sphericalshape of normal cellular components of the blood. It is 25-40 microns inlength, with a flagellum. As such, is anticipated that the lightscattering properties of trypanosomes will be readily distinguished fromthose of normal components of the vasculature.

Blood cells infected with the parasite Plasmodium falciparum may bedifferentiated from other cells in the vasculature using differentiallight scatter at 10 degrees (complexity) and polarized light scatter at90 degrees (lobularity) based on the pigmentation of the parasite(Mendelow et al. (1999) Br. J. Haematology 104:499-503).

Example 2 Detection of Biological Targets in Vessels Using ElectricalImpedance and Dielectric Properties

An untethered device configured to function in or proximal to a bloodvessel or lymph vessel may be used to detect specific biological targetsbased on changes in electrical impedance relative to cell size. As such,a cell or cells in the vessel circulation may pass through anexamination zone either incorporated within the device or in closeproximity to the device.

The examination zone may contain two or more electrodes between which anelectric current flows. As each cell passes through the electric currentin the examination zone, it displaces its own volume of conducting fluid(i.e. plasma), momentarily increasing the impedance within theexamination zone. This change in impedance produces a tiny butproportional current fluctuation that can be converted into a voltagepulse. The amplitude of this pulse is directly proportional to thevolume of the cell that produced it. As such, the device may detectchanges in electrical impedance and convert this information into volumeinformation that may be compared with preset algorithms defining, forexample, the volume of normal blood cells or cells foreign to thecirculation such as bacteria or circulating neoplastic cells.

Cellular components of the blood may be differentiated based on volumeusing electrical impedance as described herein and/or commonly practicedusing a Coulter counter. For example, platelets range in volume from 2to 20 femtoliters (fL) whereas red blood cells range in volume from70-90 fL (Hauser (2001) International Waldenstrom's MacroglobulinemiaFoundation). Neutrophils and eosinophils range in volume from 160 to 450fL while monocytes range in volume from 90 to 160 fL. By comparison,bacteria may be as small as 1 fL whereas a circulating tumor cell may beas large as 2000 fL. As such, changes in the electrical impedance in theexamination zone may be used to differentiate between various componentsof the blood.

A MEMS resembling a miniaturized Coulter counter may be incorporatedinto the device described herein and may be constructed using thinplatinum electrodes with a sensing zone of, for example, 20-100 microns(see, e.g., Zheng et al. (2006) Proceedings of 2006 InternationalConference on Microtechnologies in Medicine and Biology, IEEE, Okinawa,Japan, 9-12 May, 2006; Gao et al. (2003) Proceedings of the 25^(th)Annual International Conference of the IEEE EMBS, Cancun, Mexico, Sep.17-21, 2003).

Alternatively, cellular components of the blood may be differentiatedusing electrical impedance spectroscopy. In this instance, theelectrical impedance of a given cell is obtained by applying impulsesover a range of frequencies from, for example, 10 Hz to 10 MHz andmeasuring the impulse response. The resulting spectrum is characteristicof a given cell type. For example, T lymphocytes exhibit resonance at1.0 MHz, 2.9 MHz, 3.6 MHz, 4.5 MHz, 5.5 MHz, and 6.3 MHz while Blymphocytes exhibit resonance at 0.6 MHz, 1.7 MHz, 4.3 MHz, 5.0 MHz, 5.8MHz, and 6.3 MHz (Liu et al. (1998) IEEE: Proceedings of the 20^(th)Annual International Conference of the IEEE Engineering in Medicine andBiology Society, Vol. 20, No. 4, 1881-1884).

A component capable of micro electrical impedance spectroscopy may begenerated using MEMS and/or Lab-on-a-chip technology and incorporatedinto the untethered device described herein (see, e.g., Sun et al.(2007) Meas. Sci. Technol. 18:2859-2868; Mohanty et al.,Microtechnologies in Medicine and Biology 485-488).

Normal and cancerous lymphocytes may be distinguished by differences inthe relative capacitance and conductivity of their respective cellmembranes using dielectric spectroscopy (Feldman et al. (2003) IEEETransactions on Dielectrics and Electrical Insulation 10:728-753).

Example 3 Detection of Biological Targets in Vessels Using InfraredSpectroscopy

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect specific biologicaltargets based on infrared spectroscopy imaging. As such, a cell or cellsin the vessel circulation may pass through an examination zone eitherincorporated within the device or in close proximity to the device. Thecell or cells are illuminated in the examination zone by anelectromagnetic energy source emitting radiation at infraredwavelengths. The device measures the optical interactions of theelectromagnetic energy with the cell or cells, such as absorbance as afunction of wavelength. The absorbance information is captured by thedevice and either processed internally or sent wirelessly to an externalprocessor. In real time, the captured information is compared withpreset algorithms defining, for example, the infrared absorbanceproperties of normal blood cells and circulating tumor cells.

Infrared spectroscopy is a nondestructive photonic technique thatprovides a rapid measure of sample chemistry. A tissue or cell containsvarious chemical components with characteristic infrared spectra,including proteins, nucleic acids, carbohydrates and lipids. Thesespectra are created when a molecule converts infrared radiation intomolecular vibrations. These vibrational movements create bands in aspectrum that occur at specific wavelengths (cm⁻¹). Subtle differencesin the chemical composition of a tissue or cell can be distinguished bysubtle changes in the spectra. Chemical concentrations may be quantifiedby spectral absorbance properties at specific wavelengths, while subtlemolecular structural changes may be indicated by spectral peak shifts,band shapes and relative intensity changes occurring across thespectrum.

Infrared covers the electromagnetic spectrum from wavelengths of 0.78 to1000 μm. In the context of infrared spectroscopy, wavelength may beexpressed as wavenumber with units of cm⁻¹, such that the wavenumber isequal to the reciprocal of the wavelength in centimeters. For analysisof tissue and cells, for example, spectral data may be taken atwavenumbers between 3500 and 1000 cm⁻¹, corresponding to wavelengthsbetween 2.8 μm and 10 Kim.

Infrared spectroscopy has been used, for example, to distinguish normalepithelial cells from cancerous epithelial cells in the prostate.Glandular epithelial cells in the prostate are the primary cell typeinvolved in prostate adenocarcinoma and can be found in the circulationas a result of tumor metastasis. The infrared spectra of malignantprostate epithelial cells can be distinguished from normal epithelialcells at a variety of different wavenumbers or spectral biomarkersranging from 966 to 3290 cm⁻¹ and can be further distinguished from, forexample, lymphocytes (Fernandez et al. (2005) Nat. Biotech. 23:469-474).As such, the device may contain an electromagnetic energy source capableof emitting infrared radiation at wavelengths/wavenumbers in the rangedescribed above and may be a laser diode or diodes emitting at aspecific wavelength or a type of tunable lead salt laser, for example.

Infrared spectroscopy may also be used to detect bacteria in the blood.For example, Fourier Transfer Infrared (FT-IR) Spectroscopy may be usedto distinguish Streptococcus pneumoniae, Haemophilus influenzae, andMorazella catarrhalis bacteria in serum using a spectral range ofwavenumbers from 4000 to 800 cm⁻¹ (U.S. Pat. No. 6,379,920 B1). H.influenzae, for example, exhibits increased absorbance at 1077 cm⁻¹relative to serum alone or other bacteria tested. Alternatively, FT-IRdata may be obtained at various frequency ranges, such as, for example,3000-2800 cm⁻¹, 1800-1500 cm⁻¹, 1500-12000 cm⁻¹ 1200-900 cm⁻¹ and900-700 cm⁻¹ and spectra obtained in these various ranges compared withknown spectra of various bacteria (see, e.g., Oberreuter et al. (2002)Int. J. Syst. Evol. Microbiol. 52:91-100).

Example 4 Detection of Biological Targets in Vessels Using AcousticImaging

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect specific biologicaltargets based on ultrasound. As such, a cell or cells in the vesselcirculation may pass through an examination zone either incorporatedwithin the device or in close proximity to the device. The cell or cellsin the examination zone are exposed to acoustic waves. The devicemeasures the interactions of the acoustic waves with the cell or cells.

Acoustic imaging uses sound waves rather than light waves to generate animage. As such, a sound wave may be sent through a piece of quartz orglass coated with a thin layer of piezoelectric material that resonatesat a specific frequency, for example, 1 GHz, and through a lens to scana cell or cells (Ouellette (2004) The Industrial Physicist June/July:14-17). The sound waves are reflected back up through the lens andpiezoelectric material which serve as detector and amplifier. Thereflected sound waves are recorded electronically and may be useddirectly to compare cellular profiles. Alternatively, the recorded soundwaves may be converted into an image.

The resolution of acoustic imaging is dependent upon the frequency ofsound used for imaging. As such, standard ultrasound imaging uses soundwaves ranging in frequency from 3-10 MHz, but does not provide cellulardetail. Higher frequency ultrasound in the range of 20-100 MHz may beused to detect changes in cellular structures in tissues and cells,although individual cells are still not easily resolved. For example,cells undergoing mitosis and cells undergoing apoptosis in response to achemotherapeutic agent, for example, exhibit increased backscatteredsignal relative to normal cells (Baddour et al. (2002) UltrasonicsSymposium IEEE 2:1639-1644). Cellular resolution may be attained usingsound waves ranging in frequency from 100 MHz to 2 GHz, comparable tothe range used for acoustic microscopy, for example (Schenk et al.(1988) J. Histochem. Cytochem. 36:1341-1351). The latter corresponds towavelengths of 15 to 0.75 microns in water, the medium through whichultrasound and acoustic imaging are done.

Photoacoustic imaging, in which ultrasound detection is combined withoptical stimulation, may also be used to image objects (see, e.g. Wygantet al. (2005) IEEE Ultrasonics Symposium 1921-1924). In this process,the optical absorption properties of a material are imaged by detectingthe ultrasound emitted when a cell is illuminated with a laser. Theemitted ultrasound is due to the brief thermal expansions that occurwhen the laser energy is absorbed by the cell. Those regions that aremore optically absorbent will generate a stronger acoustic signal. Laserpulse widths, for example, of 10 ns and wavelengths between 600 nm and1000 nm may be used for photoacoustic imaging of cells. A singlemechanically scanned piezoelectric transducer or a capacitivemicromachined ultrasonic transducer array, for example, may be used todetect the laser generated ultrasound (see, e.g. Wygant et al. (2005)IEEE Ultrasonics Symposium 1921-1924).

Photoacoustic imaging may also be used to detect flowing cells in vivo(see, e.g. Zharov et al. (2006) SPIE Newsroom 10.1117/2.1200609.0391).As such, a cell or cells are irradiated with one or several focusedlaser beams operating at different wavelengths ranging, for example,from 415 to 2300 nm. An ultrasound transducer is used to recordlaser-induced acoustic waves.

Example 5 Detection of Biological Targets in Vessels Using ThermalImaging

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect specific biologicaltargets based on thermal imaging. As such, a cell or cells in thecirculation may pass through an examination zone either incorporatedwithin the device or in close proximity to the device. Thermal energy orinfrared radiation emitted from a cell or cells in the examination zoneis detected by the device using infrared photosensors made of, forexample, indium gallium arsenide or mercury cadmium telluride. Thethermal information is captured by the device and either processedinternally or sent wirelessly to an external processor. In real time,the captured information is compared with preset algorithms defining,for example, the thermal properties of normal blood cells andcirculating tumor cells.

Infrared thermography may be used to characterize tissues and cells. Forexample, infrared thermography has been used to monitor mitochondrialheat production of human adipocytes and yeast in response to agents thateither activate or inhibit cellular thermogenesis (see, e.g., U.S. Pat.No. 6,881,584). As such, infrared thermography may enabledifferentiation between normal and abnormal cells. For example, highlyproliferative malignant tumor cells often have decreased mitochondriabut higher metabolic activity due to compensatory increases inglycolytic ATP production in place of normal, more efficient oxidativephosphorylation (Gourley et al. (2005) Biomed. Microdevices 7:331-339).In contrast, benign or low grade malignant cells may have an increasednumber of mitochondria. Differences in mitochondrial number and functionmay be distinguishable using infrared thermography.

Example 6 Detection of Biological Targets in Vessels Using PhotothermalImaging

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect specific biologicaltargets based on photothermal imaging. As such, a cell or cells in thecirculation may pass through an examination zone where they areilluminated by an electromagnetic energy source. The device measures thethermal response and related effects taking place directly in a cell orcells as a result of non-radiative relaxation of the absorbedelectromagnetic energy in heat. The thermal information is captured bythe device and either processed internally or sent wirelessly to anexternal processor. In real time, the captured information is comparedwith preset algorithms defining, for example, the photothermalproperties of normal blood cells and circulating tumor cells.

Photothermal imaging may be used to distinguish between a white bloodcell, a red blood cell, and a circulating tumor cell in vivo (see, e.g.Zharov et al. (2006) J. Cell. Biochem. 97:916-932). Basic informativeparameters provided by photothermal spectroscopy include an absorptioncoefficient similar to those in conventional absorption spectroscopy,but several orders of magnitude more sensitive. Light absorbed intocells is measured directly through thermal phenomena.

A cell or cells may be irradiated, for example, with a short, focusedpump laser pulse (415-2300 nm) leading to an increase in temperature oflocal cellular absorbing structures. The temperature distribution istransformed into a refraction distribution. Time-resolved monitoring oftemperature-dependent variations in the cells refractive index isrealized with thermolens or phase contrast imaging with a CCD camera anda second collinear laser pulse at 639 nm (Zharov et al. (2006) J. Cell.Biochem. 97:916-932).

As such, correlations between specific photothermal imaging parameters,such as cell shape, and photothermal response parameters, such asamplitude, shape and duration, and morphologic cell type may be used todifferentiate between, for example, “rigid” red blood cells versus“flexible” red blood cells or circulating tumor cells versus normalwhite blood cells. As such, photothermal imaging may differentiatebetween flexible normal red blood cells and rigid Plasmodium-infectedred blood cells. Red blood cells may be differentiated from white bloodcells based on the amplitude of the integral photothermal responses,which are proportional to the cells' average absorption and differ˜30-40 fold for red blood cells and white blood cells (Zharov et al.(2006) J. Cell. Biochem. 97:916-932).

In addition, photothermal imaging is able to reveal the subcellularstructures of a red blood cell versus a white blood cell based onspecific distribution of chromophores (Galanzha et al. (2007) World J.Gastroenterol. 13:192-218). For example, hemoglobin associated with redblood cells has a smooth distribution whereas cytochromes or otherabsorbing biomolecules in white blood cells have a localizeddistribution.

Photothermal imaging associated with an untethered device may also beused to detect red blood cells that have been infected with the malariaparasite, Plasmodium falciparum. Red blood cells infected with P.falciparum accumulate light-absorbing hemozoin granules in the digestivevacuole of the parasite (Cowman et al. (1991) J. Cell. Biol.113:1033-1042). Hemozoin is the chemically inert crystalline substancethat is visible using standard light microscopy in stages that areactively degrading hemoglobin, such as trophozoites, schizonts andgametocytes. The monomeric, potentially toxic heme is released duringproteolysis of red blood cell hemoglobin and, as the parasite is unableto cleave the porphyrin ring, it is ‘detoxified’ by conversion to theinsoluble hemozoin polymer. As such, it is anticipated that theincreased sensitivity of photothermal imaging over standard absorbancespectroscopy will enable differentiation of normal and malaria-infectedred blood cells.

Example 7 Detection of Biological Targets Using Visible Light Absorptionand Refraction

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect specific biologicaltargets based on visible light absorption. As such, a cell or cells inthe circulation may pass through an examination zone where they areilluminated by visible light. The device captures the image of a cell orcells in the examination zone using a photosensor such as, for example,a CCD or CMOS camera. The image is captured by the device and eitherprocessed internally or sent wirelessly to an external processor. Inreal time, the captured information is compared with preset algorithmsdefining, for example, image and shape characteristics of normalcirculating cells and abnormal or foreign cells.

Red blood cells infected with the malaria parasite may be detected usingvisible light and phase imaging (Cowman et al. (1991) J. Cell. Biol.113:1033-1042). The parasite survives by digesting hemoglobin in the redblood cell and converts the toxic heme to hemozoin, the later of whichforms brown crystalline structures that are readily detected by lightmicroscopy. As such, a device emitting visible light may detect anddistinguish infected red blood cells from normal red blood cells basedon absorbance properties of the hemozoin. In addition, red blood cellsin general may be detected based on light absorption and scatteringusing conventional bright field imaging under the conditions of flowusing high speed data capture with a CCD or CMOS sensor (see, e.g.,Zharov et al. (2006) J. Biomed. Opt. 11:054034-1-4; U.S. Pat. No.5,934,278).

Trypanosomes may be distinguished from other components of the bloodusing visible light and phase imaging (Nolan et al. (1997) J. Biol.Chem. 272:29212-29221). The morphology of the protozoan is very distinctfrom that of normal blood cells. The protozoan is elongated, from 25 to40 um in length with a flagellum while normal blood cells arepredominantly spherical in shape. As such, the shape of a trypanosome asdetermined by visible light imaging can be readily distinguished fromnormal cells.

Similarly, cells may be imaged using quantitative phase contrast mappingwhich can reveal an objects surface with vertical resolution at thenanometer scale (Emery et al. (2007) J. Physics 61:1317-1321).

Cells may also be imaged using refractive index tomography (see, e.g.Choi et al. (2007) Nature Methods; advance online publication Aug. 12,2007). In this instance, quantitative phase images from time-dependentinterference patterns by the frequency shifting of a reference beamrelative to the sample beam. A laser beam with a wavelength, forexample, of 633 nm is divided into a sample and a reference path with abeamsplitter. A tilting mirror is used to vary the angle of illuminationof the sample. The reference beam passes through a modulator shiftingthe frequency to a longer wavelength. When the reference beam and thesample beam are recombined, an interference pattern forms at the imageplane. The interference pattern is captured with a CCD or CMOS sensorand the phase images are them calculated by applying phase-shiftinginterferometry.

Example 8 Detection of Biological Targets Using Autofluorescence

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect specific biologicaltargets based on autofluorescence. As such, a cell or cells in thevessel circulation may pass through an examination zone incorporatedwithin part of the device or in close proximity to the device, such asthe local bypass or reservoir described herein. The cell or cells areilluminated in the examination zone with a focused beam of light. Thebeam may be a form of electromagnetic energy such as, for example, whitelight, laser light, X-rays, or infrared radiation. The device detectscellular autofluorescence induced by the electromagnetic energy. Theautofluorescence information may be captured by a photosensor such as,for example, a CCD (charge coupled device) and/or a CMOS (complementarymetal oxide semiconductor) sensor. Disclosure of autofluorescencemethods and related devices and systems is found in U.S. applicationSer. Nos. 11/895,563, 11/895,564, 11/895,562, 11/895,565, 11/895,566,11/895,567, 11/895,560, and 11/895,561.

A pathogen or pathogens may be detected in the vasculature viaautofluorescence induced, for example, by electromagnetic energy.Naturally occurring autofluorescence in bacteria, for example, isderived from biomolecules containing fluorophores, such as porphyrins,amino acids tryptophan, tyrosine, and phenylalanine, and the coenzymesNADP, NADPH, and flavins (Koenig et al. (1994) J. Fluoresc. 4:17-40; Kimet al. (2004) IEEE/EMB Magazine January/February 122-129). Theexcitation maxima of these biomolecules lie in the range of 250-450 nm(spanning the ultraviolet/visible (UV/VIS) spectral range), whereastheir emission maxima lie in the range of 280-540 (spanning the UV/VISspectral range; Ammor (2007) J. Fluoresc. published on-line ahead ofpublication).

An untethered device may be used to detect pathogens associated withblood infections or septicemia, for example. Gram-negative entericbacilli, Staphylococcus aureus, and Streptococcus pneumoniae are themost common pathogens in the United States associated with micronemiaand sepsis. Staphylococcus aureus may be detected by autofluorescenceusing a device emitting electromagnetic energy at a wavelength, forexample, of 488 nm (Hilton (1998) SPIE 3491:1174-1178). Optionally,Staphylococcus aureus may be distinguished from, for example,Escherichia coli and Enterococcus faecalis based on emission spectrainduced by excitations at 410-430 nm (Giana et al. (2003) J. Fluoresc.13:489-493; Ammor (2007) J. Fluoresc. published on-line ahead ofpublication). Similarly, Streptococcus pneumoniae, may be detected usingfluorescence spectroscopy at excitation wavelengths of 250 and 550 nmand emission wavelengths of 265 and 700 nm (Ammor (2007) J. Fluoresc.published on-line ahead of publication).

A number of other bacteria may be identified based on autofluorescence.For example, bacteria associated with community acquired pneumonia,Legionella anisa and Legionella dumoffii, autofluoresce blue-white whenexposed to long-wave (365-nm) UV light (Thacker et al. (1990) J. Clin.Microbiol. 28:122-123). Bacillus spores will autofluoresce when excitedby UV irradiation at a wavelength of 352 nm (Laflamme et al. (2006) J.Fluoresc. 16:733-737). Clostridium sporogenes, Pseuodomonas aeruginose,Pseudomonasfluorescens, Kocuria rhizophila, Bacteroides vulgatis,Serratia marcescens, and Burkholderia cepacia emit yellow-greenfluorescent signal when illuminated with blue light (Sage et al. (2006)American Biotechnology Laboratory 24:20-23). Enterococcus faecalis andStaphylococcus aureus may be differentiated based on their respectiveautofluorescence in response to excitation spectra of 330-510 nm andemission spectra of 410-430 nm (Ammor (2007) J. Fluoresc. publishedon-line ahead of publication). P. aeruginosa may be detected byautofluorescence using a device emitting electromagnetic energy at awavelength, for example, of 488 nm (Hilton (1998) SPIE 3491:1174-1178).P. aeruginosa contains a pigment called pyocyanin which appears blue invisible light and may also be used for detection.

Autofluorescence of endogenous porphyrins may also be used to detectbacteria. A number of bacteria produce protoporphyrins, includingPropinibacterium acnes, Bacillus thuringiensis, Staphylococcus aureus,and some strains of Clostridium, Bifidobacterium, and Actinomyces(Koenig et al. (1994) J. Fluoresc. 4:17-40). Bacteria may also bedetected using fluorescence lifetimes measured at 430, 487, and 514 nmafter selective excitation at 340, 405, and 430 nm (Bouchard et al.(2006) J. Biomed. Opt. 11:014011, 1-7).

Autofluorescence may also be used to detect members of the fungi family.For example, Candida albicans irradiated with electromagnetic energy atwavelengths of 465-495 nm autofluoresces at an emission wavelength of515-555 nm (Mateus et al. (2004) Antimicrob. Agents and Chemother.(2004) 48:3358-3336; Graham (1983) Am. J. Clin. Pathol. 79:231-234).Similarly, Aspergillus niger and Aspergillus versicolor may be detectedusing autofluorescence in response to excitation at 450-490 nm andemission at 560 nm (Sage et al. (2006) American Biotechnology Laboratory24:20-23; Graham (1983) Am. J. Clin. Pathol. 79:231-234).

An untethered device may be used to detect and ablate parasites in theblood stream. For example, autofluorescence associated with the foodvacuole of the malaria parasite Plasmodium spp. may be used to detectinfected red blood cells with in the blood stream (Wissing et al. (2002)J. Biol. Chem. 277:37747-37755). As such, an untethered device mayinduce autofluorescence of parasites at a wavelength, for example, of488 nm (Wissing et al. (2002) J. Biol. Chem. 277:37747-37755).

Example 9 Detection of Biological Targets Using Properties ofMitochondria

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect specific biologicaltargets based the properties of intracellular mitochondria.

A biocavity nanolaser may be used for optical phenotyping of humanmitochondria (see, e.g. Gourley & Naviaux (2005) IEEE: J. SelectedTopics in Quantum Electronics 11:818-826). This method may be used todetect submicrometer particles by nanosqueezing light into photon modesimposed by the ultrasmall dimensions of the submicrometer laser cavity.As such, mitochondria from normal and abnormal cells may bedifferentiated.

For example, the mean diameter of a normal mitochondria ranges from 680to 730 nm while diseased mitochondria from a cancer cell, for example,exhibit a larger mean diameter in the range of 750 to 830 nm. Inaddition, the mitochondria in the cancer cell have a very chaotic,unorganized and random distribution within the cytosol as compared withnormal cells. As such, the lasing spectra of mitochondria may be used todifferentiate between normal and abnormal cells flowing in thecirculation (see, e.g. Gourley et al. (2005) Biomedical Microdevices7:331-339).

Optionally, autofluorescence may be used to detect and imagemitochondria (see, e.g., Sikder et al. (2005) Photochem. Photobiol.81:1569-1571). Redox fluorometry may be used to measure the levels ofpyridine nucleotides in the mitochondria, which may reflect differencesin cellular metabolic state and activity. As such, autofluorescenceassociated with reduced pyridine nucleotides (nicotinamide adeninedinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate(NADPH) may be measured in the region of 450 nm after excitation at 366nm.

Example 10 Pattern and Cell Shape Recognition

The untethered device captures information regarding the properties ofcells in a blood vessel or a lymph vessel. The information is eitherprocessed internally by the device or sent wirelessly to an externalprocessor. The information processing results in identification of acell as normal or abnormal, leading to a decision regarding the need forinitiation of the ablation process.

Pattern recognition and cell shape algorithms may be used in theinformation processing. Various methods have been described for imageand shape analysis of cells and subcellular components of cells (see,e.g., U.S. Pat. No. 5,107,422; U.S. Pat. No. 5,790,691; U.S. Pat. No.6,956,961 B2; U.S. Pat. No. 7,151,847 B2; U.S. Patent Application2005/0251347 A1; U.S. Patent Application 2006/0039593 A1; Fei-Fei et al.(2006) IEEE Transactions on Pattern analysis and Machine Intelligence28:594-611; Martin et al. (2004) IEEE Transactions on Pattern analysisand Machine Intelligence 26:530-549; Olson et al. (1980) Proc. Natl.Acad. Sci. USA 77:1516-1520; Schneider, et al (1995) Biorheology32:237-238).

Pattern recognition classifies patterns based on either prior knowledgeor on statistical information extracted from the patterns. The patternsto be classified may be groups of measurements or observations, definingpoints in an appropriate multidimensional space. As such, a patternrecognition system may consist of a sensor that gathers information orobservations to be classified or described; a feature extractionmechanism that computes numeric or symbolic information from theobservations; and a classification or description scheme that does theactual work of classifying or describing the observations, based onextracted features. The classification or description scheme may bebased on a set of patterns or a training set that have already beenclassified or described. The resulting learning strategy ischaracterized as supervised learning. Alternatively, the system mayengage in unsupervised learning in that the system is not given priorlabeling of patterns, but instead establishes the classes itself basedon the statistical regularities of the patterns.

A Texture Analyzing System may be used to distinguish various cells inthe vasculature based on the granularity of the cell or cells (Bins etal. (1981) Cytometry 1:321-324). As such, the imaged components of thecells are measured with a gray scale with 33 intervals ranging fromblack (level 0) to white (level 99) and a histogram is generated.

For example, mature WBC (neutrophils, eosinophils, basophils andlymphocytes) have a dense nuclear structure and therefore low counts. Incontrast, monocytes have a looser, less dense nuclear structure and highcounts. The cytoplasm of eosinophils and neutrophils is very granularand is reflected in the combination of high positive and low negativecounts. Smaller values are seen in the cytoplasm of lymphocytes,monocytes and basophils. Similarly, granulometries may be used toidentify red blood cells infected with the malarial parasite (Dempster &DiRuberto (2001) IEEE 5:V291-V294).

A neural network algorithm may be used to classify normal and abnormalcomponents of the vasculature. For example, a neural network based fuzzyclassifier may be used to automatically distinguish mature and immaturewhite blood cells with a recognition rate of 90-92% (Uebele et al.(1995) IEEE Transactions on Systems, Man, and Cybernetics 25:353-361).In this instance, optically screened white blood cells may be classifiedinto 12 categories of mature and immature white blood cells usingfeatures such as area and perimeter. A neural network based shaperecognition algorithm using nuclear radius and curvature features may bealso be used to automatically distinguish mature and immature whiteblood cells (He & Wilder (2002) IEEE: Proceedings of the Second JointEMBS/BMES Conference, Houston, Tex., USA Oct. 23-26, 2002). Similarapproaches may be used to classify and recognize lymphocytes, monocytes,neutrophils, eosinophils and basophils (see, e.g. Kovalev et al. (1996)IEEE: Proceedings of ICPR 1996 371-375). Alternatively, data regarding,for example, the infrared or light scattering properties of mature andimmature cells may be the basis for the neural network based patternrecognition.

Subcellular phenotypes of a cell, for example, nuclei or mitochondria,may be automatically identified using different machine learningmethods, including Support Vector Machines (SVMs), Artificial NeuralNetworks (ANN) or a combination of ANN and Bayesian learning (Conrad etal. (2004) Genome Res. 14:1130-1136). As such, image or spectralinformation regarding a subcellular component of a cell may be processedand used to distinguish various cell types.

Example 11 Methods for Capturing and Sequestering Biological Targets inVessels

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may include the capacity to capture andsequester specific biological targets from the vasculature optionallyinto a reservoir (and/or local bypass) for future analysis. As such, thedevice may have the capacity to capture a biological target beforeanalysis in the examination zone, at which point the biological targetis identified as normal or abnormal and either released back intocirculation or sequestered into a reservoir or holding chamber.Alternatively, the device may have the capacity to analyze thebiological target as it passes through the examination zone, at whichpoint the biological target is identified as normal or abnormal andeither allowed to keeping moving or is captured and sequestered in areservoir.

A specific cell or cells may be captured and moved into a reservoir(and/or local bypass) of the device using the natural fluid flow withinthe vessel. As such, the opening and closing of strategically placedvalves within the device may be used to manipulate the flow of cells,allowing for selective sequestration of targeted cells into thereservoir.

Size exclusion may be used to detect and capture circulating tumor cells(see, e.g., Mohamed et al. (2004) IEEE Transactions on Nanobioscience,3:251-256). As such, the device may have a fixed diameter or sieve, forexample, through which normal blood components may pass but larger cellssuch as, for example, circulating tumor cells, are retained and eitherimmediately ablated or shunted to a reservoir. Alternatively, the devicemay have a moveable aperture that allows for controlled changes indevice diameter to capture and release or sequester a cell or cells asappropriate.

Alternatively, a cell or cells may be captured and sequestered based onintrinsic magnetic properties. For example, red blood cells infectedwith the malaria parasite P. falciparum may be captured based on themagnetic properties of the infected cells (Moore et al. (2006) FASEB J.20:747-749). During development in the red blood cell, the malariaparasite digests hemoglobin leading to the accumulation of toxic heme.In the process of incorporating the heme into hemozoin crystals, theheme is converted to a high-spin ferriheme with increased magneticproperties. P. falciparum infected red blood cells may be enriched40-fold relative to other blood components using a magnetic fieldintensity of 1.426 T (Zimmerman et al. (2006) Am. J. Trop. Med. Hyg.74:568-572). As such, malaria-infected cells may be identified using themethods described here in and subsequently captured relative to otherblood components, for example, using net volume magnetic susceptibility.

Optionally, a cell or cells may be captured and sequestered usingsuction. For example, cells along the surface of a lumen may be pulledaway from the surface using a plunger system that sucks the cells into asuction chamber (see, e.g. U.S. Patent Application 2005/0272972 A1). Assuch, the device may include a plunger that when retracted causes a cellor cells to be sucked directly into a reservoir or into a tube (e.g.local bypass) that optionally leads to a reservoir.

Optionally, a form of optical trapping or optical tweezers may be usedto move or sort a cell or cells into a reservoir. For example, red bloodcells may be moved using a focused laser beam from, for example, a He—Nelaser (Grover et al. (2000) Optics Express 7:533-538). A focused laserexerts both a scattering force and a gradient force on a cell in itspath and these forces can be manipulated to move an object. Opticaltweezers may also be used to differentiate between normal andPlasmodium-infected red blood cells (Dharmadhikari et al. (2004) OpticsExpress 12:1179-1184).

Alternatively, dielectrophoresis may be used to move or sort a cell orcells in a microdevice (see, e.g. Chiou et al. (2005) Nature436:370-372; Holmes & Morgan (2002) European Cells Materials 4:120-122).Dielectrophoresis (DEP) refers to the force on a cell in a non-uniformelectrical field produced by an array of microelectrodes. Depending uponhow negative and positive DEP forces are manipulated, a specific cell orcell type may be concentrated from a heterogeneous mix. Alternatively,different cell types may be sorted along the path of a device based onsize and dielectric properties of the cellular membrane.

Example 12 Surveillance of Biological Targets in the Vasculature

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used over a period of time to monitorspecific biological targets in the vasculature using the detectionmethods described herein. As such, a cell or cells in the vesselcirculation may pass through an examination zone either incorporatedwithin the device or in close proximity to the device. A cell or cellsmay be, for example, a bacterium, a platelet, a red blood cell, a whiteblood cell, a circulating tumor cell or a combination thereof. The cellor cells are analyzed in the examination zone using one or more of themethods described herein. The device captures information regarding thecell or cells and either processes the information internally or sendsthe information wirelessly to an external processor. The capturedinformation is compared with preset algorithms defining, for example,the properties of a normal versus an abnormal or foreign cell. Thedevice may keep track of or count the number of normal, abnormal and/orforeign cells, for example, over a period of time. Optionally, thedevice may monitor changes in cell morphology or chemistry over a periodof time.

The untethered device may be used, for example, to monitor the relativenumbers of normal biological components of blood or lymph vessels.Changes in the normal cell counts may be indicative of disease. Forexample, a normal white blood cell count ranges from 4,500 to 10,000cells per microliter of blood. Leukopenia, a dangerously low white bloodcell count below 2,500 cells per microliter, may be indicative of HIV orother viral infection, an autoimmune disorder such as lupus, or a bonemarrow disease, such as leukemia or myelodysplastic syndromes (MayoClinic (2006) Low white blood cell count (leukopenia)).

As another example, the normal level of platelets in the blood rangesfrom 150,000 to 350,000 per microliter. As the platelet count decreasesbelow a normal level, the ability of the body to prevent bleedingdecreases. As such, tiny red dots may appear in the skin, bruising mayoccur more easily, the gums may bleed, and blood may appear in the stoolor urine. When the platelet count falls to 10,000 to 5,000, lifethreatening bleeding in the digestive tract or brain may occur even whenthere is no injury (Merck Manual (1997) p. 755; Berkow et al, eds).

The surveillance information acquired by the untethered device may beused to monitor disease progression. For example, the device may be usedin a patient or patients with cancer to monitor for the appearance ofcirculating tumor cells in the vasculature. Circulating tumor cells maybe indicative of metastasis and may suggest a need for changes in thetreatment regime. For example, the detection of circulating tumor cellsin melanoma patients who are clinically “disease-free” indicates diseaserecurrence, tumor cell spreading, and a high potential for distantmetastasis, and enables identification of high-risk melanoma patients(Hoon (2004) Nat. Clin. Pract. Oncol. 1:74-75).

The appearance of circulating tumor cells may also be indicative of longterm prognosis for the patient. For example, breast cancer patients withlevels of circulating tumor cells equal to or higher than 5 cells per7.5 milliliters of blood have a shorter median progression-free survival(2.7 months vs. 7.0 months) and shorter overall survival (10.1 monthsversus greater than 18.0 months) as compared with breast cancer patientswith less than 5 cells per 7.5 milliliters of blood (Cristofanilli etal. (2004) N. Engl. J. Med. 351:781-791).

The untethered device may also be used to monitor the effectiveness of atreatment regime. For example, the device may be used to monitor thetiter of bacteria in the vasculature in response to antibiotictreatment. Similarly, the device may be used to monitor the white bloodcell count of an HIV-AIDS patient in response to anti-viral treatments.

Alternatively, the device may be used to monitor side effects associatedwith a specific treatment regime. For example, treatment of HIV-AIDSwith anti-viral nucleoside reverse transcriptase inhibitors (NRTIs)induces severe changes in lymphocyte mitochondrial morphology andfunction (Tolomeo et al. (2003) J. Clin. Pathol. 56:147-151). As such,the device may monitor lymphocyte mitochondria using the methodsdescribed herein to monitor the toxic effects of HIV treatment.

In another example, the device may monitor the effects of cancer therapyon normal blood components. Both chemotherapy and radiotherapy reducewhite blood cell counts, making an individual more prone to infection.Similarly, red blood cell and platelet counts may be lowered in responseto chemotherapy (Mayo Clinic (2005) Low blood cell counts: Side effectof cancer treatment). As such, the device may monitor the blood in realtime and provide feedback to the physician and/or patient as to theblood cell counts, allowing for prompt treatment.

Example 13 Methods for at Least Partially Inactivating BiologicalTargets in Vessels

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to at least partially inactivate abiological target in response to detection and recognition of thebiological target as abnormal, for example. Alternatively, a secondcomponent downstream of the untethered device, for example, may be usedto at least partially inactivate a biological target in the vesselsand/or in a local bypass and/or reservoir. As such, once the abnormalcell has been detected and recognized by the untethered device, theuntethered device may nearly simultaneously initiate an inactivationprocess while the cell is still effectively in the examination zone.Alternatively, once the abnormal cell has been detected and recognizedby the untethered device, a downstream component may be signaled toinitiate inactivation at a future time consistent with passage of theabnormal cell in proximity to the downstream component based, forexample, on the measured flow rate within the vessel. In some instances,focused energy sufficient to at least partially inactivate an abnormalcell may be directed only at the cell of interest. Alternatively, asegment of the vessel lumen containing at least the abnormal cell may betargeted.

An untethered device configured to function in or proximal to a bloodvessel or lymph vessel may use ultraviolet radiation to at leastpartially inactivate a biological target. For example, many pathogensare inactivated or killed by UV germicidal irradiation (Anderson et al.(2000) IEEE Transactions on Plasma Science 28:83-88; Hancock et al.(2004) IEEE Transactions on Plasma Science 32:2026-2031). UV lightranges from UVA (400-315 nm), also called long wave or ‘blacklight’; UVB(315-280 nm), also called medium wave; and UVC (<280 nm), also calledshort wave or ‘germicidal’.” Escherichia coli may be partially orcompletely inactivated, for example, by exposure to a UV electromagneticenergy source at wavelengths of 100-280 nm (Anderson et al. (2000) IEEETransactions on Plasma Science 28:83-88). Alternatively, Escherichiacoli as well as Salmonella enteritidis, for example, may be inactivatedusing pulsed broad-spectrum electromagnetic energy with high UV contentfrom, for example, a Xenon lamp (Anderson et al. (2000) IEEETransactions on Plasma Science 28:83-88). In this instance, targetedbacteria are subjected to 100-1000 pulses of broad-spectrum light witheach pulse lasting, for example, 85 ns and having, for example, a poweroutput of 10 MW. Viruses may be inactivated using UV irradiation (Tseng& Li, (2007) J. Occup. Envirn. Hyg. 4:400-405). Fungi, such asAspergillus flavus and Aspergillus fumigatus, may also be inactivatedusing UV germicidal irradiation at, for example, 12-98 mJ/cm² (Green etal. (2004) Can. J. Microbiol. 50:221-224).

Optionally, the device may emit electromagnetic energy at a wavelengthor wavelengths within the visible spectrum to at least partiallyinactivate a biological target. For example, Staphylococcus aureus andPseudomonas aeruginosa may be inactivated using a wavelength of 405 nmat doses ranging, for example, from 1-20 J/cm² (Guffey et al. (2006)Photomed. Laser Surg. 24:680-683). Pseudomonas aeruginosa as well asEscherichia coli may be partially inactivated using, for example, awavelength of 630 nm at 1-20 J/cm² (Nussbaum et al. (2002) J. Clin.Laser Med. Surg. 20:325-333). Similarly, a number of oral bacteria,including Acinobacillus actinomycetemcomitans, Fusobacterium nucleatum,Porphromonas gingivalis, Pnevotella intermedia, and Streptococcussanguis, may be partially inactivated using a diode 665 laser at 100 mWat energy densities ranging from 10 J/cm² to 22 J/cm² (Chan et al.(2003) Lasers Surg. Med. 18:51-55). Alternatively, a pathogen, forexample Escherichia coli, may be at least partially inactivated orkilled using a 810 nm diode laser with doses ranging from 130-260 J/cm²(Jawhara et al. (2006) Lasers Med. Sci. 21:153-159).

Similarly, visible light may be used to at least partially inactivate avirus. For example, a virus may be at least partially inactivated usinga very low power laser emitting 80 femtosecond pulses at a wavelength of425 nm and frequency of 80 MHz (Tsen et al. (2007) Virol. J. Vol. 4,published on line ahead of publication; Tsen et al. (2007) J. Physics:Condensed Matter Vol. 19, published on line ahead of publication). Underthese conditions, the viruses are inactivated through impulsivestimulated Raman scattering, which induces vibrations within themicroorganism sufficient to disrupt normal function.

Alternatively, energy may be used that disrupts the function of hemeiron porphyrins associated with iron uptake and utilization,inactivating iron dependent bacteria such as Escherichia coli andSalmonella (U.S. Pat. No. 6,030,653). Pathogens may be inactivated byirradiating the surface with visible and near infrared light havingwavelengths of approximately 465 nm, 600 nm, and 950 nm, respectively.

Optionally, visible light energy emitted from an untethered device maybe combined, for example, with systemic administration of aphotosensitive agent (Maisch (2007) Lasers Med. Sci. 22:83-91; Jori etal. (2006) Lasers Surg. Med. 38:468-481). For example, Staphylococcusaureus and Pseudomonas aeruginosa may be inactivated using either a0.95-mW helium-neon laser (632 nm) or a 5-mWindium-gallium-aluminum-phosphate laser (670 nm) with exposure dosesranging from 0.1 to 10.0 J/cm² in combination with the bacterialsensitizing agent, toluidine blue O (DeSimone et al. (1999) Phys. Ther.79:839-846). Similarly, inactivation of bacteria by a diode 665 lasermay be enhanced, for example, by prestaining the bacteria with methyleneblue (Chan et al. (2003) Lasers Surg. Med. 18:51-55). Alternatively, afluorescing dye, for example, indocyanine green (ICG) may be used incombination with a diode laser with an emission wavelength, for example,of 808 nm, to inactive a pathogen or pathogens (Bartels et al. (1995)SPIE 2395:602-606). Optionally, a polycationic photosensitizerconjugated between, for example, poly-L-lysine and chlorin_(∈6), may beadministered and subsequently irradiated with a diode laser at 665 nm atdoses ranging from, for example, 40-160 J/cm² to kill bacteria (Hamblinet al. (2002) Photochem. Photobiol. 75:51-57). Optionally, pathogens inthe vasculature, such as, for example, Staphylococcus aureus andStaphylococcus epidermidis, may be at least partially inactivated usingenergy from, for example, an argon-ion pumped dye laser (wavelength of630 nm with total light dose of 180 J/cm²) in combination with5-aminolevulinic acid or Photofrin (Karrer et al. (1999) Lasers Med.Sci. 14:54-61; Nitzan et al. (1999) Lasers Med. Sci. 14:269-277).

An untethered device configured to function in or proximal to a bloodvessel or lymph vessel may use laser-induced thermal energy to at leastpartially inactivate a biological target. For example, lasers arecommonly used to treat cancers, such as basal cell skin cancer and thevery early stages of some cancers, such as cervical, penile, vaginal,vulvar, and non-small cell lung cancer (National Cancer Institute (2004)Laser in Cancer Treatment FactSheet). As such, circulating tumor cells,for example, may be at least partially inactivated by laser-inducedthermal energy.

A variety of lasers with varied excitation wavelengths and penetrationpotential may be used to generate electromagnetic energy sufficient toat least partially inactivate, for example, a circulating tumor cell orcells (Burr et al. (2004) Interventional Technologies for Tissue VolumeReduction, October 2004). For example, circulating tumor cell or cellsmay be ablated using a carbon dioxide (CO₂) laser (10,600 nm, 0.1-0.2 mmpenetration depth). Melanoma and cervical cancer cells may be ablatedwith a CO₂ laser using a power output ranging, for example, from 40 W to80 W (Gibson, et al (2004) Br. J. Surg. 91:893-895; Bekassy et al.(1997) Lasers. Surg. Med. 20:461-466). Alternatively, cancer cells maybe ablated by a Yttrium-Aluminium-Garnet (YAG) laser with Neodymium (Nd,1064 nm or 1320 nm, 3-4 mm penetration depth), Erbium (Eb, 2940 nm, with<0.1 mm penetration depth), or Holmium (Ho, 2070 nm). For example,colorectal adenoma cells and lung cancer cells may be ablated using anNd:YAG (1064 nm) with maximal power output of 100 W (Norberto et al.(2005) Surg. Endosc. 19:1045-1048; Hansen et al. (2006) Minim. InvasiveTher. Allied Technol. 15:4-8). Alternatively, cancer cells may beablated by diode lasers (600-1600 nm), argon laser (488 nm and 514 nm,1-1.5 mm penetration depth), or an excimer laser (180-350 nm,cell/tissue disintegration). As such, the untethered device may containone or more of the lasers described herein as an optical energy sourcefor use in at least partially inactivating a biological target such as,for example, a circulating tumor cells.

Alternatively, a circulating tumor cells or cells, for example, may beablated by electromagnetic energy emitted from a laser in combinationwith a photosensitizing agent in a process termed photodynamic therapy(PDT; National Cancer Institute (2004) Laser in Cancer TreatmentFactSheet). For example, a patient may be injected with aphotosensitizing agent such as, for example, Photofrin or5-aminolevulinic acid, which after a few days concentrates in thecancerous cells. Electromagnetic energy from, for example, a laser isthen used to activate the photosensitizing agent which has a subsequenttoxic effect on the cancer cell or cells and results in cell death.

Laser-induced thermal energy generated by a CO₂ or Nd:YAG laser may alsobe used to at least partially inactivate a pathogen in the vasculature(see, e.g. Bartels et al. (1995) SPIE 2395:602-606). Escherichia coli0157:H7, for example, is extremely sensitive to heat with a maximumtolerance of approximately 35 degrees centigrade (U.S. Pat. No.6,030,653). Staphylococcus aureus may be partially inactivated or killedusing high-power Nd:YAG laser radiation between 50 and 300 W with laserpulse frequencies of 5 to 30 Hz and pulse energies from 2 to 30 J,resulting in a range of energy densities from 800 to 270 J/cm² (Yeo etal. (1998) Pure Appl. Opt. 7:643-655). Similarly, Staphylococcusepidermidis, may be killed using pulsed radiation from a Nd:YAG laserwith an exposure of 1000-2000 J/cm² (Gronqvist et al. (2000) LasersSurg. Med. 27:336-340).

The untethered device may use electromagnetic energy in the form ofx-rays to at least partially inactivate biological targets in thevasculature. As such, the device may contain a miniature X-ray emitter,such as that described in U.S. Patent Application 2004/0218724 A1.Alternatively, the device may contain radioisotopes such as cobalt 60,cesium 137, or europium 152, for example, that emit strong gamma raysand may be used to ablate cancerous cells. Optionally, the device maycontain other intrinsically radioactive isotope such as those that mightbe used for brachytherapy, including, for example, iodine 125, iodine131, strontium 89, phosphorous, palladium, or phosphate (National CancerInstitute (2004) Radiation Therapy for Cancer FactSheet).

X-ray therapy or radiotherapy is routinely used to treat almost everytype of solid tumor, including cancers of the brain, breast, cervix,larynx, lung, pancreas, prostate, skin, spine, stomach, uterus, or softtissue sarcomas (National Cancer Institute (2004) Radiation Therapy forCancer FactSheet). For example, breast cancer cells may be ablated usinga miniature electron beam-driven x-ray source at doses of 5 to 20 Gy(Ross et al. (2005) Breast Cancer Res. 7:110-112). As such, radiotherapymay be used to at least partially inactivate circulating tumor cellsderived from, for example, these solid tumors.

Pathogens may also be at least partially inactivated by x-rayelectromagnetic energy. For example, pathogens such as Escherichia coli0157:H7, Salmonella, and Campylobacter jejuni may be at least partiallyinactivated or killed using cobalt-60 gamma radiation at doses of 0.5 to3 kGy (Clavero et al. (1994) Applied Environ. Microbiol. 60:2069-2075).

Alternatively, particle beam energy may be used to at least partiallyinactivate a biological target. For example, Salmonella, Yersinia, andCampylobacter may be at least partially inactivated using acceleratedelectrons with doses of irradiation ranging from 1-3 kGy (Sarjeant etal. (2005) Poult. Sci. 84:955-958). Similarly, Bacillus endospores maybe at least partially inactivated using electron beam irradiation withdoses ranging from 5 to 40 kGy (Helfinstine et al. (2005) AppliedEnviron. Microbiol. 71:7029-7032).

Alternatively, a cancer cell or cells may be ablated by using particlebeam energy using a type of linear accelerator. Medical LINAC (linearaccelerator-based external beam radiotherapy), for example, accelerateselectrons to kinetic energies from 4 to 25 MeV using microwaveradiofrequency waves at 10³ to 10⁴ MHz (Podgorsak Chapter 5). A LINACmay provide X-rays in the low megavoltage range (4 to 6 MV).Alternatively, a LINAC may provide both X-rays and electrons at variousmegavoltage energies, for example, two photon energies (6 and 18 MV) andseveral electron energies (6, 9, 12, 16, and 22 MeV; Podgorsak Chapter5).

The untethered device may use electromagnetic energy in the formmicrowave or radiofrequency waves to at least partially inactivatebiological targets in the vessels. The microwave range includesultra-high frequency (UHF) (0.3-3 GHz), super high frequency (SHF) (3-30GHz), and extremely high frequency (EHF) (30-300 GHz) signals. Microwaveradiation at a frequency of 29.8 GHz (Ka-band), for example, may be usedto at selectively kill bacteria with minimal damage to healthy humancells (Ardnt et al. Microwave radiation—Therapeutic application for cureof subcutaneous bacterial infections. Space Life Sciences).

The untethered device may alternatively use the heating properties offocused ultrasound to at least partially inactivate biological targetsin the vasculature. Ultrasound causes tissue damage through conversionof mechanical energy into heat and through cavitation. Above a thresholdof 56 degrees centigrade, for example, rapid thermal toxicity isachieved and cells are irreversibly inactivated or killed.High-intensity focused ultrasound (HIFU) uses short exposures of focusedultrasound that rapidly increases cellular temperature above 80 degreescentigrade and is used for ablation, for example, of hepatocellularcarcinoma, prostate carcinoma, bladder and kidney cancers (see, e.g.,Kennedy et al. (2003) Br. J. Radiology 76:590-599). As such, it isanticipated that short exposures to high-intensity focused ultrasoundmay be used to at least partially ablate targeted cells within thevessels.

Optionally, an untethered device may emit a laser-generated stress wavesufficient to disrupt a biological target. For example, stress wavessufficient to disrupt cell membranes may be generated with an ArF (193nm) or a KrF (248 nm) eximer laser. Peripheral blood mononuclear cellsand red blood cells may be damaged using, for example, 5 pulses ofpressure ranging from 700 to 1000 bar (Lee et al. (1999) IEEE Journal ofSelected Topics in Quantum Electronics 5:997-1003). As such, the devicemay use a laser to generate a stress wave sufficient to at leastpartially ablate a targeted cell.

An untethered device may emit electrical energy in a focused area in thevasculature sufficient to ablate a biological target. For example,cancer cells in suspension may be at least partially ablated usingelectrical pulses sufficient to induce irreversible electroporation ofthe cells (Miller et al. (2005) Technol. Cancer Res. Treat. 4:699-705).As such, a cell or cells may be exposed, for example, to 10-30, 0.3millisecond pulses at 500 to 2500 V/cm to induce at least partialinactivation.

Examples 14 Devices for Detection and Ablation of Biological Targets inVessels

An untethered device configured to function in or proximal to a bloodvessel or a lymph vessel may be used to detect, register and at leastpartially inactivate a biological target. FIG. 11 shows an illustrativediagram of a system including a device 400. The device 400 is placed inor proximal to a vessel 410 of a patient 420. The device 400 may workautonomously, containing all of the components necessary to detect,register and/or inactive a biological target. Alternatively, the device400 may be linked wirelessly to a remote (optionally portable),processor and/or power supply 430 and/or external computer processor 450and/or power supply.

In one configuration, the processor and/or power supply 430 is wornexternally by the patient 420 on, for example, a belt 440. Optionally,the processor and/or power supply 430 may be held by the patient 420 in,for example, a pocket, a backpack or a purse. Alternatively, theprocessor and/or power supply 430 may be surgically implanted in thepatient 420 (see, e.g., U.S. Pat. No. 6,409,719). Optionally, theprocessor and/or power supply 430 may be linked to the device 400 via awire or wires.

FIG. 12, FIG. 13, FIG. 14, and FIG. 15. show illustrative configurationsof systems including one or more untethered devices configured tofunction in the lumen of a blood vessel or lymph vessel to detect,register and optionally at least partially inactivate a biologicaltarget.

FIG. 12A shows an illustrative configuration of an untethered device 460for the detection and at least partial inactivation of a biologicaltarget in the lumen of a vessel 410. In this configuration, theuntethered device 460 may be a hollow cylinder that when placed in alumen of a vessel 410 allows for the flow of fluid and cells 500 and 510through the central core 470 of the cylinder. The cylinder may bereversibly positioned in the vessel using inflatable pouches 480.Alternatively, the cylinder may be positioned in the vessel using one ormore retractable hooks or barbs, for example, that latch on to the lumenof the vessel 410. The hollow cylinder contains a detection and/orablation unit 490, which optionally contains one or more of a powersource, control circuitry, one or more energy sources, one or moresensors and a processor. Control of the device may be completelyself-contained or at least partially controlled wirelessly by anexternal user.

As normal cells 500 and abnormal cells 510 pass through the central core470 of the untethered device 460, the detection and/or ablation unit 490emits a first energy beam, such as, for example, an electromagnetic oracoustic energy which interacts with the cell in a characteristicmanner. In this context, abnormal cells 510 may be, for example,pathogens, pathological cells or cancerous cells as described herein.The detection and ablation unit 490 processes the information regardingthe interaction of the normal cell 500 and abnormal cell 510 with afirst energy beam and analyzes whether the cell is normal or abnormaland almost simultaneously emits a second energy beam sufficient to atleast partially inactivate the abnormal cell 510.

As illustrated in FIG. 12B, the system may include a second untethereddevice 465 positioned downstream from the first device 460. As such, thefirst device 460 emits an energy beam from the detection and/or ablationunit 490 to analyze a passing biological target, and determines whetherthe biological target is normal or abnormal. The first device 460 maysend a signal to the second device 465 to initiate emission of an energybeam from a second detection and/or ablation unit 495 sufficient to atleast partially inactivate a biological target at a time in the futureconsistent with the passage of an abnormal target through the seconddevice 465.

FIG. 13 shows an illustrative configuration of a system including anuntethered device 460 with the capability of controlling fluid and cellflow in the lumen of a vessel 410 for the detection and optionally atleast partial inactivation of a biological target. In thisconfiguration, the device 460 is a hollow tube with an exit aperture 520that may be opened or closed to control the flow of fluid and cells inthe vessel. As such, the exit aperture 520 of the device 460 may be inan open position 525 allowing for free flow of fluid and cells, as shownin FIG. 13A. Cells pass through the device 460 unabated and aremonitored and optionally destroyed by the detection and/or ablation unit490. Alternatively, as shown in FIG. 13B, the exit aperture 520 mayperiodically shift to the closed position 530 providing more time, forexample, for the analysis of cells in the device 460 and/or opportunityfor targeted inactivation. The device may automatically open and closethe exit aperture 520 at a fixed rate. Alternatively, the exit aperture520 may open and close depending upon signals sent from the detectionand/or ablation unit 490 in response to detecting an abnormal cell, forexample. Optionally, opening and closing of the exit aperture 520 may bedictated externally by the patient, physician, or other medicalpractitioner.

FIG. 14 shows an illustrative configuration of an untethered device 540with the capability of temporarily trapping and at least partiallyinactivating abnormally large biological targets in the lumen of avessel 410. In this configuration, size exclusion may be used to trap anabnormally large cell 560 such as, for example, a circulating tumorcell. As such, cells pass through the hollow tube of the device 540.Within the device 540 is a choke point 545 which narrows the diameter ofthe hollow tube. As such, smaller cells 510 and 550, such as, forexample, red and white blood cells, may pass through the device whereasan abnormally large cell 560 will slowed down or become trapped, atwhich point the cell is bombarded with an energy beam sufficient to atleast partially inactivate the target.

FIG. 15A and FIG. 15B show alternative illustrative configurations ofsystems including an untethered device for the detection and at leastpartial inactivation of a biological target in the lumen of a vessel410.

FIG. 15A shows an illustrative configuration of an untethered device 570in the lumen of a vessel 410 in which the main body of the device is ahollow tube configured using a diamond-patterned mesh structure similarto, for example, a stent (see, e.g. Lally et al. (2005) J. Biomechanics38:1574-1581; U.S. Patent Application 2006/0074479 A1). In thisconfiguration, one or more detection and/or ablation units 575 aredistributed around the hollow tube. Each detection and/or ablation unit575 may have the capability of emitting energy, sensing a response,inducing ablation, or a combination thereof. Optionally, the system mayinclude an exterior (to the vessel lumen) unit 580 which may provideprocessing and/or power capabilities. The exterior unit 580 may beattached to the outer surface of the vessel with one or more hooks orbarbs 585, for example.

FIG. 15B shows an illustrative configuration of system including anuntethered device 590 in the lumen of a vessel 410 in which the mainbody of the device is a hollow tube configured from one or more parallelrings 595. Alternatively the hollow tube may be formed from a spiral,for example, of a single or multiple pieces of material. As shown, eachring 595 of the device 590 may include an energy emitting unit 600 and asensing unit 610. Alternatively, units 600 and 610 may have both energyemitting and sensing capabilities. In this configuration, the device mayhave an ablating unit 620 downstream from the energy emitting units 600and the sensing units 610. As such, a cell may pass through the hollowtube where the energy emitting unit 600 and the sensing unit 610register the cell as normal or abnormal. If the cell is abnormal asignal is sent to the ablating unit 620 to initiate cell inactivation ata time in the future consistent with the time needed for a cell to movefrom one end of the tube to the other. The device 590 may be used inconjunction with an exterior unit 630 which optionally surrounds theexterior of the vessel 410 like a sleeve and provides, for example,additional processing and/or power capabilities.

FIG. 16 and FIG. 17 show illustrative configurations of systemsincluding one or more untethered devices configured as units to functionalone or together in the lumen of a blood vessel or lymph vessel todetect, register and optionally at least partially inactivate abiological target.

FIG. 16A shows an illustrative configuration of a device 640 which isattached to the interior surface of a vessel 410 by virtue of a hook orbarb 650. The untethered device 640 may be configured to act autonomousor be controlled by an external user. The untethered device 640 maymonitor the flow of fluid and normal cells 500 and abnormal cells 510.The device 640 detects abnormal cells 510 based on the characteristicresponse of normal cells 500 and abnormal cells 510 to a beam of energy660. On detection of one or more abnormal cells, the device 640 emits asecond beam of energy 660 sufficient to at least partially ablate thedetected abnormal cell 510 before the cell exits the inactivation area.

In an alternative illustrative configuration of the system, an energyemitting unit 670 may be paired with a sensing unit 680, as shown inFIG. 16B. In this configuration, the energy emitting unit 670 andsensing unit 680 are each attached to the interior surface of a vessel410 by virtue of one or more hook or barb 650. The energy emitting unit670 emits a beam of energy 660 which irradiates, for example, anabnormal cell 510. The sensing unit 680 measures the response of theabnormal cell 510 to the beam of energy 660 and sends a signal back tothe energy emitting unit 670 to initiate cell inactivation, whereuponthe energy emitting unit 670 emits a second beam of energy 660sufficient to at least partially inactivate a biological target.

Alternatively, one or more illustrative system may include an energyemitting and sensing unit 690 paired with a downstream ablating unit 700as shown in FIG. 16C. The energy emitting and sensing unit 690 and theablating unit 700 are optionally attached to the interior surface of avessel 410 by virtue of one or more hook or barb 650. An abnormal cell510 is irradiated by a beam of energy 660 emitted from the energyemitting and sensing unit 690 and registered as abnormal. A signal issent to the ablating unit 700 to initiate cell inactivation at a time inthe future consistent with the time needed for a cell to move from theenergy emitting and sensing unit 690 to the ablating unit 700. Theablating unit 700 emits a second energy beam 710 sufficient to at leastpartially inactivate a biological target.

FIG. 17A shows an illustrative configuration of a system including threeseparate units; an energy emitting unit 720, a sensing unit 680, and adownstream ablating unit 700, all of which are attached to the interiorsurface of a vessel 410 by virtue of one or more hook or barb 650. Inthis configuration, an abnormal cell 510, for example, is irradiated byan energy beam 660 from an energy emitting unit 720. The response of theabnormal cell 510 to the energy beam 660 is detected by the sensing unit680 which may relay information to the ablating unit 700 as to whethercell inactivation should be initiated. The ablating unit 700 emits anenergy beam 710 at a time in the future consistent with the time neededfor a cell to move from the sensing unit 680 to the ablating unit 700.The energy emitting unit 720, the sensing unit 680, and the downstreamablating unit 700 may be used in conjunction with an exterior unit 630which optionally surrounds the exterior of the vessel 410 like a sleeveand provides, for example, processing and/or power capabilities.

FIG. 17B shows an alternative illustrative configuration of a system inwhich an energy emitting and sensing unit 690 is paired with adownstream ablating unit 730. In this configuration, the ablating unit730 is a hollow tube positioned within a vessel 410 using inflatablepouches 480, for example. The ablating unit 730 has an aperture 740which may be closed to trap biological targets identified forinactivation, and/or for additional sensing optionally prior toinactivation, for example. An abnormal cell 510, for example, isidentified by the energy emitting and sensing unit 690 as abnormal and asignal is sent to the ablating unit 730. The downstream ablating unit730 initiates closure of the aperture 740 at a time in the futureconsistent with the time needed for the abnormal cell 510 to reach theablating unit 730. Once the abnormal cell 510 is trapped, the ablatingunit 730 emits an energy beam 710 sufficient to at least partiallyinactive a biological target.

FIG. 18, FIG. 19, and FIG. 20 show illustrative configurations ofsystems configured to function proximal to a blood vessel or lymphvessel to detect, register and optionally at least partially inactivatea biological target. In these examples, the system may incorporatedevice including a sleeve which at least partially encircles a vessel.

FIG. 18A shows an illustrative configuration of a device 750 which atleast partially encircles the exterior of a vessel 410 (see, e.g., U.S.Pat. No. 6,106,477). FIG. 18B shows an illustrative configuration ofoptional components of the device 750. A hinge 760 may be used to openthe device 750 to enable it to at least partially encircle a vessel 410.The device may have an energy emitting unit 780 coupled with a sensingunit 770 which scans cells through the wall of a vessel 410. Methodshave been described for imaging cells in vivo from the exterior of avessel (see, e.g., Galanzha et al. (2007) World. J. Gastroenterol.13:192-218; U.S. Pat. No. 7,264,794 B2). The device 750 may also containa processing and/or power supply unit 790.

FIG. 19 shows various illustrative configurations of one or more systemsincluding a device configured to function proximal to a blood vessel orlymph vessel. In these examples, a sleeve 810 constructed from amesh-like, breathable, biocompatible material is used to encircle theexterior of a vessel 410 (see, e.g., U.S. Patent Application2006/0149348 A1). Various components are optionally attached to thissleeve. In FIG. 19A, a device 800 consists of a sleeve 810 that isattached along a seam 820 to itself and/or the vessel 410 using areversible wet/dry adhesive such as that derived from gecko and mussel(e.g. geckel), for example (see, e.g., Lee et al. (2007) Nature448:338-342). Alternatively, a magnetic strip or Velcro-like materialmay be used to close the sleeve. Attached to the sleeve 810 is an energyemitting unit 830 and a sensing unit 840. Alternatively, a single unitcapable of energy emitting and sensing may be attached to the sleeve810.

In FIG. 19B, a device 801 may have a sleeve 810 attached to itselfand/or to the vessel 410 using, for example, sutures 850 (optionallystaples and/or another kind of medical closure known to those of skillin the art). In this configuration, a constrictor (e.g. compression)band 860 is positioned downstream from the sleeve 810. The constrictorband 860 may be used to restrict the flow of fluid and cells through thevessel 410 optionally for brief periods of time. The constrictor band860 may be an inflatable tube that upon inflation closes down thediameter of the vessel 410. Alternatively, the constrictor band 860 mayconstitute a band of biocompatible material that may be controllablytightened and loosened, optionally using one or more ratchets, forexample.

The constrictor band 860 may be activated by inputs from a wire 870connected, for example, to the sensing unit 840. Alternatively, theconstrictor band 860 may be activated by a wireless signal form thesensing unit 840, and/or from one or more external sources. Theconstrictor band 860 may be used to slow down cells to facilitateanalysis by the energy emitting unit 830 and the sensing unit 840.Alternatively, the constrictor band 860 may be activated after anabnormal cell has been identified to trap the cell prior to inactivationfrom an energy beam emitted, for example, from the energy emitting unit830.

In FIG. 19C, a device 802 is configured with a first sleeve 810 and asecond sleeve 890 which is positioned downstream of the first. Attachedto the second sleeve 890 is an ablating unit 900 that is optionallyattached by a wire 870 to the sensing unit 840. In this configuration,the sleeve 810 is attached to itself and/or the vessel 410 using aclosure device 880. A closure device may include, for example, a snap, ahook, or Velcro-like material. A cell or cells in the vessel 410 areanalyzed, for example, by the energy emitting unit 830 and the sensingunit 840. When an abnormal cell is registered by the sensing unit 840, asignal is sent to the downstream ablating unit 900 by a wire 870.Alternatively, a wireless signal may be sent to activate the ablatingunit 900. The ablating unit 900 emits an energy beam sufficient to atleast partially inactivate a biological target at a time in the futureconsistent with the passage of the cell into the target zone of theablating unit 900.

FIG. 20 shows various illustrative configurations of systems including adevice configured to function proximal to a blood vessel or lymph vesseland optionally to sequester a biological target into a reservoir, forexample, for future analysis. In FIG. 20A, a device 803 is configuredwith a sleeve 810 constructed from a breathable, biocompatible material.The sleeve 810 is used to encircle the exterior of a vessel 410. Anexpandable reservoir 930, for example, a sack constructed frombiocompatible material, is attached to the sleeve 810 by a tube-likestructure 920. The tube 920 opens into the vessel 410 through anadjustable valve 910. In this configuration, a constrictor band 860 maybe positioned downstream of the sleeve 810 to restrict the flow of fluidand cells for brief periods of time. A cell in the vessel 410 isanalyzed by the energy emitting unit 830 and the sensing unit 840. If acell or cells is identified that should be sequestered, a signal is sentto the constrictor band 860 via a wire 870, for example. The constrictorband 860 closes down the diameter of the vessel 410, trapping cells inthe vicinity of the valve 910. The valve 910 is triggered to open,allowing a cell or cells to flow into the tube 920 and into thereservoir 930. The movement of cells into the reservoir 930 may bepassive, optionally driven by the flow pressure of the vessel 410.

FIG. 20B shows an alternative configuration in which device 804 includesa reservoir 940 located in a remote position relative to the vessel 410.For example, the remote reservoir 940, made from silicon or otherbiocompatible material, may be positioned on or near the surface of theskin, for example, allowing for easy access by a physician,veterinarian, or other medical practitioner using a syringe, for example(see, e.g. Diegelmann et al. (1987) J. Leukocyte Biol. 42:667-672). Theremote reservoir 940 is attached to the sleeve 810 through a tube 920that traverses the length between the position of the sleeve 810 on avessel 410 and the position of the reservoir 940. As such, a cell orcells is analyzed by an energy emitting unit 830 and a sensing unit 840.If a cell or cells is identified that should be sequestered, a wirelesssignal is sent to the constrictor band 860. The constrictor band 860closes down the diameter of the vessel 410, trapping cells in thevicinity of a valve 910. The valve 910 is triggered to open, allowing acell or cells to flow into the tube 920 and down its length to thereservoir 940. The movement of cells into the remote reservoir 940 maybe passive, optionally driven by the flow pressure of the vessel 410.Alternatively, a type of peristaltic motion, for example, may be usedalong the length of the tube 920 to move cells into the remote reservoir940.

FIG. 21, FIG. 22, FIG. 23, and FIG. 24 show illustrative configurationsof systems including a device configured to function proximal to a bloodvessel or lymph vessel to detect, register and optionally at leastpartially inactivate a biological target. In these examples, the devicemay incorporate a shunt (e.g. local bypass), allowing for analysis ofall or part of the cells flowing through a vessel 410.

FIG. 21 shows an illustrative configuration of a device 805 in which asleeve 810 is combined with a shunt 960. FIG. 21A shows an exterior viewof the device 805 encircling a vessel 410. The sleeve 810 is reversiblyattached to itself and/or the vessel 410 along the seam 820 using themethods described herein. The shunt 960 may have sharp, optionallyscalpel-like and/or large-bore needle-like ends 970 that pierce thevessel 410 as the sleeve 810 is closed around the vessel 410. In thismanner, openings are created in the wall of the vessel 410 allowing forpassage of some or all of the vessel contents into the shunt 960.Attached to the shunt may be an energy emitting unit 980 and a sensingunit 990. The shunt 960 itself may be made of clear, opticallycompatible material, allowing for unobstructed imaging of a cell orcells from the outside surface of the shunt 960. Alternatively, aportion of the energy emitting unit 980 and/or the sensing unit 990 maybe incorporated into the inner surface of the shunt.

FIG. 21B shows an illustrative configuration of the interior view of adevice 805 in which a sleeve 810 is combined with a shunt 960. As such,a subset of cells in vessel 410 may enter the shunt 960 through anopening 1000 generated by piercing the surface of the vessel 410optionally as described in FIG. 21A and/or known in the art. An abnormalcell 510, for example, may be targeted with an energy beam 660 emittedfrom the energy emitting unit 980. The cellular response is detected bythe sensing unit 990. The sensing unit 990 sends a signal to the energyemitting unit 980 to activate a second energy beam 660 configured to atleast partially inactivate the abnormal cell 510. Untargeted cells passthrough the shunt 960 and back into the flow of vessel 410.

FIG. 22A and FIG. 22B show illustrative configurations of systemsshowing the interior view of devices 950 and 955 configured with a shunt960 (e.g. local bypass) to analyze all or a subset of cells in a vessel410. In FIG. 22A, a device 950 includes a shunt 960 attached to a vessel410 and contains an energy emitting unit 980 and a sensing unit 990.Access to and from the vessel 410 to the shunt 960 is controlled byvalves 1005 at either end of the shunt 960. As such, when the valve 1005is opened, a cell or cells may pass into the shunt 960. The cell, forexample an abnormal cell 510, may pass through an examination zone 965within the shunt 960.

Within the examination zone, the abnormal cell 510 is irradiated, forexample, with electromagnetic energy from a laser unit 1010. The laserunit 1010 may be comprised of one or more quantum dot lasers ornanolasers, for example (see, e.g., PHYSORG (2007) news 95617101; Nozakiet al. (2007) Optics Express 15:7506-7514). Alternatively, acousticenergy may be emitted from laser unit 1010. A specific sensing device1020, such as, for example, a CCD or CMOS sensor, captures informationregarding the interaction of the abnormal cell 510 with theelectromagnetic energy emitted by a laser unit 1010. Methods have beendescribed, for example, for the scaling of CMOS sensor technology downto the nanometer scale (Chang et al. (2003) Proceedings of the IEEE91:1860-1873). The shunt 960 may also contain a processor and/or powerunit 1030. Alternatively, the shunt 960 may be connected wirelessly orby wire to a remote or external processor and/or power supply.

Once the abnormal cell 510 has been identified as abnormal, a signal isoptionally sent to initiate cell inactivation. As such, the laser unit1010 may emit a second energy beam sufficient to at least partiallyinactivate the abnormal cell 510. Optionally a second energy emittingunit 1040 may be used to emit energy sufficient to at least partiallyinactivate the abnormal cell 510.

In FIG. 22B, a device 955 includes a shunt 960 configured to allow forsequestering of specific biological targets into a reservoir. The shunt960 is attached to a vessel 410 and contains an energy emitting unit 980and a sensing unit 990. Access to and from the vessel 410 to the shunt960 is controlled by valves 1005 at either end of the shunt 960. Assuch, when the valve 1005 is opened, a cell or cells may pass into theshunt 960. Additional valves 1005 may be placed at either end of theexamination zone 965. The cell, for example an abnormal cell 510, maypass through an examination zone 965 within the shunt 960. The abnormalcell 510 is analyzed by the laser unit 1010 and the sensing unit 1020 asdescribed in FIG. 22A.

The abnormal cell 510 may be targeted for sequestration. As such anadditional valve 1005 may open into tube 1070 connected to a reservoir.The reservoir may be proximal or remote relative to the analysis deviceas described herein. The cell or cells may passively move into the tube1070 based on flow pressure. Alternatively, a cell or cell may bespecifically moved into the tube 1070 by a force 1060 emitted from aforce unit 1050. The force may be part of an optical trap, a DEP trap ormagnetic in nature, as described herein. Once the appropriate cell orcells have been sequestered, the valve 1005 associated with the tube1070 may be closed and other valves 1005 downstream opened to allowuntargeted cells in the shunt 960 to rejoin the flow in vessel 410.

FIG. 23 and FIG. 24 show illustrative configurations of systemsincluding an artificial vessel shunt which is secured between the endsof a vessel 410. FIG. 23A shows an exterior view of this configurationin which the artificial vessel shunt 1080 is attached to the free endsof a vessel 410 by a connector 1090, such as, for example, a cinch.Alternatively, the artificial vessel shunt 1080 may be attached to thevessel 410, for example, by a tight fitting with the lumen of the vessel410 and barbs on the end of the artificial vessel shunt 1080 (see, e.g.U.S. Pat. No. 7,175,637). The artificial vessel shunt 1080 has an energyemitting unit 980 and a sensing unit 990 associated with it.

FIG. 23B shows an illustrative configuration of the interior of anartificial vessel shunt 1080 attached to both ends of vessel 410 usingconnectors 1090. The artificial vessel shunt 1080 may have one or morevalves 1005 to control the flow of fluid and cells. Within theexamination zone, an abnormal cell 510 as referenced in FIG. 22 isirradiated, for example, with electromagnetic energy from a laser unit1010. A specific sensing device 1020 captures information regarding theinteraction of the abnormal cell 510 with the electromagnetic energyemitted by a laser unit 1010. Once the abnormal cell 510 has beenidentified as abnormal, a signal is sent to initiate cell inactivation.As such, the laser unit 1010 may emit a second energy beam sufficient toat least partially inactivate the abnormal cell 510. Optionally a secondenergy emitting unit 1040 may be used to emit energy sufficient to atleast partially inactivate the abnormal cell 510. Optionally, theabnormal cell is targeted for sequestration and is moved through a valve1005 into a tube 1070 for removal to a reservoir.

FIG. 24A and FIG. 24B show alternative configurations of systemsincluding an artificial vessel in which all or a subset of the cells inthe vessel flow are analyzed. For example, in FIG. 24A, a device 1100 isinserted between the two ends of a vessel 410 using connectors 1090.Associated with the device is a shunt 960. A cell or cells passingthrough the shunt may be analyzed by an energy emitting unit 980 and asensing unit 990. If appropriate, a cell may be at least partiallyinactivated within the shunt 960. FIG. 24B shows an illustrativeconfiguration of a device 1110 which is similar to that of device 1100with the addition of a tube 1070 which allows for sequestration oftargeted cells to a reservoir 940.

The foregoing detailed description has set forth various embodiments ofthe devices and/or processes via the use of block diagrams, flowcharts,and/or examples. Insofar as such block diagrams, flowcharts, and/orexamples contain one or more functions and/or operations, it will beunderstood by those within the art that each function and/or operationwithin such block diagrams, flowcharts, or examples can be implemented,individually and/or collectively, by a wide range of hardware, software,firmware, or virtually any combination thereof. In one embodiment,several portions of the subject matter described herein may beimplemented via Application Specific Integrated Circuits (ASICs), FieldProgrammable Gate Arrays (FPGAs), digital signal processors (DSPs), orother integrated formats. However, those skilled in the art willrecognize that some aspects of the embodiments disclosed herein, inwhole or in part, can be equivalently implemented in integratedcircuits, as one or more computer programs running on one or morecomputers (e.g., as one or more programs running on one or more computersystems), as one or more programs running on one or more processors(e.g., as one or more programs running on one or more microprocessors),as firmware, or as virtually any combination thereof, and that designingthe circuitry and/or writing the code for the software and or firmwarewould be well within the skill of one of skill in the art in light ofthis disclosure. In addition, those skilled in the art will appreciatethat the mechanisms of the subject matter described herein are capableof being distributed as a program product in a variety of forms, andthat an illustrative embodiment of the subject matter described hereinapplies regardless of the particular type of signal bearing medium usedto actually carry out the distribution. Examples of a signal bearingmedium include, but are not limited to, the following: a recordable typemedium such as a floppy disk, a hard disk drive, a Compact Disc (CD), aDigital Video Disk (DVD), a digital tape, a computer memory, etc.; and atransmission type medium such as a digital and/or an analogcommunication medium (e.g., a fiber optic cable, a waveguide, a wiredcommunications link, a wireless communication link, etc.).

Those skilled in the art will recognize that it is common within the artto describe devices and/or processes in the fashion set forth herein,and thereafter use engineering practices to integrate such describeddevices and/or processes into data processing systems. That is, at leasta portion of the devices and/or processes described herein can beintegrated into a data processing system via a reasonable amount ofexperimentation. Those having skill in the art will recognize that atypical data processing system generally includes one or more of asystem unit housing, a video display device, a memory such as volatileand non-volatile memory, processors such as microprocessors and digitalsignal processors, computational entities such as operating systems,drivers, graphical user interfaces, and applications programs, one ormore interaction devices, such as a touch pad or screen, and/or controlsystems including feedback loops and control motors (e.g., feedback forsensing position and/or velocity; control motors for moving and/oradjusting components and/or quantities). A typical data processingsystem may be implemented utilizing any suitable commercially availablecomponents, such as those typically found in datacomputing/communication and/or network computing/communication systems.

The herein described subject matter sometimes illustrates differentcomponents contained within, or connected with, different othercomponents. It is to be understood that such depicted architectures aremerely exemplary, and that in fact many other architectures can beimplemented which achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” such that the desired functionality isachieved. Hence, any two components herein combined to achieve aparticular functionality can be seen as “associated with” each othersuch that the desired functionality is achieved, irrespective ofarchitectures or intermedial components. Likewise, any two components soassociated can also be viewed as being “operably connected”, or“operably coupled”, to each other to achieve the desired functionality,and any two components capable of being so associated can also be viewedas being “operably couplable”, to each other to achieve the desiredfunctionality. Specific examples of operably couplable include but arenot limited to physically mateable and/or physically interactingcomponents and/or wirelessly interactable and/or wirelessly interactingcomponents and/or logically interacting and/or logically interactablecomponents.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

For ease of reading, all values described herein, and all numericalranges described herein are approximate and should be read as includingthe word “about” or “approximately” prior to each numeral, unlesscontext indicates otherwise. For example, the range “0.0001 to 0.01” ismeant to read as “about 0.0001 to about 0.01.”

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to inventions containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

All references herein, including but not limited to patents, patentapplications, and non-patent literature are hereby incorporated byreference herein in their entirety.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

1. An untethered device comprising: one or more first energy sourceconfigured to function in, or proximal to, one or more blood vessel orlymph vessel of a subject and to provide energy configured to elicit oneor more image responses associated with the one or more blood vessel orlymph vessel; one or more sensors configured to function in, or proximalto, the one or more blood vessel or lymph vessel and to capture the oneor more image responses, and wherein the one or more sensors areconfigured to orient to the one or more first energy sources; controlcircuitry coupled to the one or more sensors and responsive to at leastpartially identify one or more targets during an expected transit timeof the one or more targets through a detection area in the one or moreblood vessel or lymph vessel at least partially based on the capturedone or more image responses; one or more inserts configured to bedisposed in the one or more blood vessel or lymph vessel and including alumen extending therethrough having a lateral dimension that decreasesat a choke point, the choke point configured to at least slow the one ormore targets based at least partially on a size thereof as the one ormore targets attempt to flow through the lumen; and one or more secondenergy source configured to provide ablation energy to the one or moretargets when the one or more targets are at least slowed by the chokepoint of the lumen responsive to the control circuitry at leastpartially identifying the one or more targets.
 2. The device of claim 1,wherein the one or more first energy source is an electromagnetic energysource.
 3. The device of claim 1, wherein the one or more first energysource is an acoustic energy source.
 4. The device of claim 1, whereinthe one or more sensors are configured to align with the one or morefirst energy sources.
 5. The device of claim 1, wherein the controlcircuitry is responsive to at least partially identify the one or moretargets at least partially based on pattern recognition.
 6. The deviceof claim 1, wherein the control circuitry is responsive to at leastpartially identify the one or more targets at least partially based onshape recognition.
 7. The device of claim 1, wherein the controlcircuitry is responsive to at least partially identify the one or moretargets at least partially based on an actual cellular image.
 8. Thedevice of claim 1, wherein the control circuitry is responsive to atleast partially identify the one or more targets at least partiallybased on relative cell size.
 9. The device of claim 1, wherein thecontrol circuitry is responsive to at least partially identify the oneor more targets at least partially based on size.
 10. The device ofclaim 1, wherein the control circuitry is responsive to at leastpartially identify the one or more targets at least partially based onsurface features.
 11. The device of claim 1, wherein the controlcircuitry is responsive to identify the target area at least partiallybased on one or more temporal-spatial locations of the one or moreidentified targets.
 12. The device of claim 1, wherein the controlcircuitry is responsive to identify the target area at least partiallybased on velocity of the one or more identified targets.
 13. The deviceof claim 1, wherein the control circuitry is responsive to identify thetarget area at least partially based on vibratory dynamic response ofthe one or more identified targets.
 14. The device of claim 1, whereinthe control circuitry is responsive to identify the target area at leastpartially based on angular response of the one or more identifiedtargets.
 15. The device of claim 1, wherein the control circuitry isresponsive to identify the target area at least partially based oninertial response of the one or more identified targets.
 16. The deviceof claim 1, wherein the control circuitry is responsive to identify thetarget area at least partially based on predicting one or more futurelocations of the one or more identified targets.
 17. The device of claim1, wherein the control circuitry is responsive to identify the targetarea by analysis of one or more characteristics of the one or more imageresponses.
 18. The device of claim 1, wherein the control circuitryselects one or more characteristics of the energy emitted by the secondenergy source responsive to one or more characteristics of the one ormore image responses.
 19. The device of claim 1, wherein the one or moresecond energy source is an electromagnetic energy source.
 20. The deviceof claim 1, wherein the one or more second energy source is an acousticsource.
 21. The device of claim 1, wherein the one or more second energysource is a particle beam energy source.
 22. The device of claim 1,wherein one or more of the one or more second energy source ispositioned down-flow from one or more of the one or more first energysource or the one or more sensors.
 23. The device of claim 1, whereinthe one or more second energy source is configured to function withinthe one or more blood vessel or lymph vessel.
 24. The device of claim 1,wherein the one or more second energy source is configured to functionproximal to the one or more blood vessel or lymph vessel.
 25. The deviceof claim 1 wherein the one or more inserts is operably responsive to thecontrol circuitry and configured to modulate at least part of an innercircumference of the one or more blood vessel or lymph vessel.
 26. Anuntethered device comprising: one or more first energy source configuredto function in, or proximal to, a lumen of one or more blood vessel orlymph vessel of a subject and to provide energy configured to elicit oneor more image responses associated with the lumen; one or more sensorsconfigured to capture the one or more image responses; control circuitrycoupled to the one or more sensors and responsive to at least partiallyidentify one or more targets during an expected transit time of the oneor more targets through a detection area in the lumen at least partiallybased on the captured one or more image responses; one or more insertincluding at least one valve operably responsive to the controlcircuitry and configured to at least partially close the one or moreinsert to trap the one or more targets in the one or more insert; andone or more second energy source responsive to the control circuitry atleast partially identifying the one or more targets and configured toemit energy selected to at least partially ablate the one or moretargets when trapped in the one or more insert.
 27. The device of claim26, wherein the one or more insert is configured to controllablymodulate at least part of the circumference of the lumen.
 28. The deviceof claim 26, wherein the one or more insert is configured to reversiblymodulate at least part of the circumference of the lumen.
 29. The deviceof claim 26, wherein the one or more insert is configured toprogrammably modulate at least part of the circumference of the lumen.30. The device of claim 26, wherein the one or more insert is configuredto narrow at least part of the circumference of the lumen such that oneor more cells traverse a localized region.
 31. The device of claim 26wherein the at least one valve is operable to open in response to thecontrol circuitry at least partially identifying the one or moretargets.
 32. The device of claim 26 wherein the at least one valve isoperable to open in response to the one or more second energy sources atleast partially ablating the one or more targets.